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WO2025124414A1 - Sonde d'imagerie moléculaire ciblant la poly(adp-ribose) polymérase, son procédé de préparation et son utilisation - Google Patents

Sonde d'imagerie moléculaire ciblant la poly(adp-ribose) polymérase, son procédé de préparation et son utilisation Download PDF

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WO2025124414A1
WO2025124414A1 PCT/CN2024/138338 CN2024138338W WO2025124414A1 WO 2025124414 A1 WO2025124414 A1 WO 2025124414A1 CN 2024138338 W CN2024138338 W CN 2024138338W WO 2025124414 A1 WO2025124414 A1 WO 2025124414A1
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程震
瞿春容
何纯丰
石慧
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Shanghai Institute of Materia Medica of CAS
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    • 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
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K49/108—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 the metal complex being Gd-DOTA
    • 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
    • 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
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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

Definitions

  • the present invention relates to radiopharmaceutical chemistry, and in particular to a class of compounds used as molecular imaging probes targeting poly ADP ribose polymerase (PARP), and a preparation method and application thereof.
  • PARP poly ADP ribose polymerase
  • PARP1 Poly (ADP-ribose) polymerase (PARP) was first discovered more than 50 years ago and is an important enzyme involved in the repair of single-strand DNA damage (SSB).
  • PARP1 is the first member of the poly (ADP-ribose) polymerase superfamily, which consists of proteins with homology to PARP1.
  • the family now has 17 members, of which 4 members - PARP1, PARP2, PARP5A and PARP5B can catalyze the formation of PAR chains.
  • PARP1 is the most numerous enzyme in the PARP family and plays the most important role in the repair of single-strand DNA damage.
  • PARP1 recognizes SSBs through its three zinc finger structures.
  • the binding of the PARP1 zinc finger structure to DNA causes conformational changes, activates PARP1, and cleaves NAD+ into nicotinamide and ADP-ribose moieties.
  • the ADP-ribose moiety is covalently attached to PARP1 or other nuclear proteins and then other ADP-ribose moieties are added to it to produce long or branched PAR chains. These negatively charged polymers recruit the DNA repair enzyme XRCC1 to the site of damage for repair.
  • 18F-BO is a 18F-labeled olaparib targeting group (references: Keliher, E.J.; Reiner, T.; Turetsky, A.; Hilderbrand, S.A.; Weissleder, R. High-Yielding, Two-Step 18F Labeling Strategy for 18F-PARP1 Inhibitors. ChemMedChem 2011 , 6(3), 424–427.
  • 18F-FTT is based on rucaparib structural modification and labeling with 18F, and has entered the clinical trial stage (references: Michel, L.S.; Dyroff, S.; Brooks, F.J.; Spayd, K.J.; Lim, S.; Engle, J.T.; Phillips, S.; Tan, B.; Wang-Gillam , A.; Bognar, C.; Chu, W.; Zhou, D.; Mach, R.H.; Laforest, R.; Chen, D.L. PET of Poly (ADP-Ribose) Polymerase Activity in Cancer: Preclinical Assessment and First In-Human Studies.
  • [64Cu]Cu-DOTA-PARP is obtained by labeling 64Cu with DOTA group modified with Olaparib (reference: Huang, T. Initial Evaluation of Cu-64 Labeled PARPi-DOTAPET Imaging in Mice with Mesothelioma. 2017, 5.).
  • the purpose of the present invention is to provide a class of molecular imaging probes targeting poly ADP ribose polymerase (PARP).
  • PARP poly ADP ribose polymerase
  • Another object of the present invention is to provide a method for preparing the molecular imaging probe targeting poly (ADP-ribose) polymerase (PARP).
  • PARP molecular imaging probe targeting poly (ADP-ribose) polymerase
  • Another object of the present invention is to provide the application of the molecular imaging probe targeting poly (ADP-ribose) polymerase (PARP).
  • PARP molecular imaging probe targeting poly (ADP-ribose) polymerase
  • the present invention adopts the following technical solutions:
  • Rx is
  • R5 is a group derived from a chelating agent that chelates with an element
  • the element is selected from elements that generate nuclear magnetic signals and elements that generate radioactive signals,
  • R3 is selected from the group consisting of a direct bond, -C1-C20 alkylene, -(( CH2 ) a- O) b- ( CH2 ) c- , -C1-20 alkenylene, -C1-20 alkynylene, -C3-20 cycloalkylene, -C5-20 arylene, -C5-20 heteroarylene, and -C3-20 heterocyclylene,
  • R 4 is selected from: H, -C1-C20 alkyl, -((CH 2 ) a -O) b -(CH 2 ) d CH 3 , -C1-20 alkenyl, -C1-20 alkynyl, -C3-20 cycloalkyl, -C5-20 aryl, -C5-20 heteroaryl, -C3-20 heterocyclyl;
  • R2 is selected from: H, -C1-C20 alkyl, -(( CH2 ) a -O) b- ( CH2 ) cCH3 , -C1-20 alkenyl, -C1-20 alkynyl, -C3-20 cycloalkyl, -C5-20 aryl, -C5-20 heteroaryl, -C3-20 heterocyclyl, or
  • R 6 and R 7 are each independently the same as defined in R 1 , or are a direct bond;
  • R2 is selected from the group consisting of: H, -C1-C20 alkyl, -(( CH2 ) a -O) b- ( CH2 ) cCH3 , -C1-20 alkenyl, -C1-20 alkynyl, -C3-20 cycloalkyl, -C5-20 aryl, -C5-20 heteroaryl, -C3-20 heterocyclyl,
  • the subscripts a, b, and c are each independently an integer from 1 to 5;
  • R 4 is selected from: H and -C1-C20 alkyl
  • the subscripts a, b, and c are each independently an integer from 1 to 5;
  • R2 is selected from: H and -C1-C20 alkyl, or
  • R 6 and R 7 are each independently the same as defined for R 1 ;
  • R2 is selected from: H and -C1-C20 alkyl.
  • the chelating agent is selected from tetraazacyclododecane tetraacetic acid (DOTA), triazacyclononane triacetic acid (NOTA), 1,4,7-triazacyclononane-1-pentanedioic acid-4,7-diacetic acid (NODAGA), 1,4,7,10-tetraazacyclododecane-1-pentanedioic acid-4,7,10-triacetic acid (DOTAGA), 2,2',2",2"-(5 2 ,13 2 -dihydroxy-5 5 ,13 5 any one of dimethyl-3,7,11,15-tetraaza-1,9(2,6)-bipyridine-5,13(1,3)-dibenzocyclohexanedione-3,7,1,11,15-tetrayl)tetraacetic acid (Dar), dimethyltriaminepentaacetic acid (DTPA), 32-
  • Dar dimethyltriaminepentaacetic
  • the element producing nuclear magnetic signal is selected from Gd, Fe, Eu, Mn, Cu, Si and Nd
  • the element producing radioactive signal is selected from 68 Ga, 99m Tc, 89 Zr, 64 Cu, 177 Lu, 90 Y, 111 In, 18 FAl, 225 Ac, 188 Re, 186 Re, 213 Bi, 44 Sc, 47 Sc, 212 Pb and 203 Pb.
  • the compound of formula Ia or Ib is selected from the following compounds:
  • the present invention further provides a method for preparing the compound of formula Ia or Ib, and the preparation route is as follows:
  • the method comprises the following steps:
  • Compound 3 is reacted with a compound containing an element selected from the group consisting of Gd, Fe, Eu, Mn, Cu, Si, Nd, 68 Ga, 99m Tc, 89 Zr, 64 Cu, 177 Lu, 90 Y, 111 In, 18 FAl, 225 Ac, 188 Re, 186 Re, 213 Bi, 44 Sc, 47 Sc, 212 Pb, 203 Pb to obtain Compound Ia, or
  • the method comprises the steps of:
  • Compound 1, HOOC-R 1 -NR 2 Boc e.g., 5-((tert-butyloxycarbonyl)amino)pentanoic acid, 5-((2-((tert-butyloxycarbonyl)amino)ethyl)amino)-5-oxopentanoic acid)
  • 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate are added to N,N-dimethylformamide, and N,N-diisopropylethylamine is added, and the mixture is reacted at room temperature for 30 minutes to 2 hours.
  • the method comprises the following steps:
  • the present invention also provides the use of the compound of formula Ia or Ib as a PARP-targeted positron emission, single photon emission or nuclear magnetic resonance imaging probe, especially the use in diseases with abnormal PARP expression, especially the use in the preparation of tumor PET imaging agents, the preparation of tumor SPECT imaging agents or the preparation of tumor MRI imaging agents.
  • the present application synthesizes a class of novel structural compounds, which can act as PARP-targeted positron emission, single photon emission or nuclear magnetic resonance imaging probes and have great application prospects in the imaging treatment of diseases such as tumors that are related to abnormal PARP expression.
  • FIG1 is a micro-PET/CT imaging effect diagram of the tumor of M6 prepared in Example 6 in A549 tumor-bearing mice, and the circle indicates the location of the tumor.
  • FIG2 is a micro-PET/CT imaging effect diagram of the tumor of M7 prepared in Example 7 in A549 tumor-bearing mice, and the circle indicates the location of the tumor.
  • the raw materials, reagents, experimental animals, etc. used in this application are conventional raw materials, reagents, experimental animals in the field and are commercially available. Animal experiments comply with the ethical requirements for experimental animals, and the equipment and methods used are conventional equipment and methods in the field.
  • the intermediate 1 (20 mg) of the previous step was added to 5 mL of DCM, and 10 mL of trifluoroacetic acid was added.
  • the reaction was carried out for 60 minutes, the solvent was dried by rotary evaporation, 2 mL of N,N-dimethylformamide was added, 100 microliters of DIPEA was added, and 40 mg of 2,2',2'-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid was added, the reaction was carried out for 24 hours, the solvent was dried by rotary evaporation, and the white solid was purified by preparative liquid chromatography to obtain 21 mg, with a yield of 73%.
  • the method was the same as step 1 of Example 1, except that 5-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-5-oxopentanoic acid was used instead of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid to obtain 63 mg of a white solid.
  • the method is the same as step 3 of Example 1, except that intermediate 2 from the previous step is used to prepare M2.
  • the method was the same as step 1 of Example 1, except that (tert-butyloxycarbonyl)glycine was used instead of 5-(4-(tert-butyloxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid to obtain 53 mg of a white solid.
  • the method is the same as step 3 of Example 1, except that intermediate 2 from the previous step is used to prepare M3.
  • the method is the same as step 1 of Example 1, except that 3-((tert-butyloxycarbonyl)amino)propionic acid is used instead of 5-(4-(tert-butyloxycarbonyl)piperazine-1-yl)-5-oxopentanoic acid to obtain 54 mg of a white solid.
  • the method is the same as step 3 of Example 1, except that intermediate 2 from the previous step is used to prepare M4.
  • the method is the same as step 3 of Example 1, except that intermediate 2 from the previous step is used to prepare M5.
  • the method is the same as step 1 of Example 1, except that 5-((tert-butyloxycarbonyl)amino)pentanoic acid is used instead of 5-(4-(tert-butyloxycarbonyl)piperazine-1-yl)-5-oxopentanoic acid to obtain 55 mg of a white solid.
  • the method is the same as step 3 of Example 1, except that the intermediate 2 from the previous step is used to prepare M6.
  • the method is the same as step 1 of Example 1, except that 6-((tert-butyloxycarbonyl)amino)hexanoic acid is used instead of 5-(4-(tert-butyloxycarbonyl)piperazine-1-yl)-5-oxopentanoic acid to obtain 55 mg of a white solid.
  • the method is the same as step 3 of Example 1, except that the intermediate 2 from the previous step is used to prepare M7.
  • the method is the same as step 1 of Example 1, except that 3-(2-((tert-butyloxycarbonyl)amino)ethoxy)propionic acid is used instead of 5-(4-(tert-butyloxycarbonyl)piperazine-1-yl)-5-oxopentanoic acid to obtain 55 mg of a white solid.
  • the method is the same as step 3 of Example 1, except that the intermediate 2 from the previous step is used to prepare M8.
  • the intermediate 1 (20 mg) of the previous step was added to 5 mL of DCM, and 10 mL of trifluoroacetic acid was added.
  • the reaction was carried out for 60 minutes, the solvent was dried by rotary evaporation, 2 mL of N,N-dimethylformamide was added, 100 microliters of DIPEA was added, and 40 mg of 2,2',2'-(10-(2-((2,5-dioxopyrrolidin-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid was added, the reaction was carried out for 24 hours, the solvent was dried by rotary evaporation, and the white solid (15 mg) was obtained by preparative liquid phase purification with a yield of 58%.
  • the method was the same as step 1 of Example 1, except that 12-((2-((tert-butoxycarbonyl)amino)ethyl)amino)-12-oxododecanoic acid was used instead of 5-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-oxopentanoic acid to obtain 60 mg of a white solid.
  • step 2 of Example 1 The method is the same as step 2 of Example 1, except that the intermediate 1 in the previous step is used to obtain 16 mg of colorless semisolid.
  • the method is the same as step 3 of Example 1, except that the intermediate 2 from the previous step is used to prepare M10.
  • Test Example 1 Determination of the lipid-water distribution coefficient LogD7.4 of M6
  • M6 probe About 30 ⁇ Ci of M6 probe was placed in a centrifuge tube containing equal volumes of PBS buffer and n-octanol. After vortexing for 15 minutes, the tube was allowed to stand for 5 minutes. The upper n-octanol phase and the lower aqueous phase were centrifuged separately. Then equal volumes of n-octanol phase and aqueous phase were taken and the ratio of the probes in the two phases was measured using a gamma counter. The LogD7.4 of M6 was -3.623 ⁇ 0.196, which has a very low lipid-water distribution coefficient compared to the currently developed PARP-targeted PET probes.
  • mice Three commercially available SPF-grade Balb/c nude mice were inoculated with A549 cells (human non-small cell lung cancer cells) in the axilla of the right forelimb.
  • A549 cells human non-small cell lung cancer cells
  • 100-150 ⁇ Ci of the M6 probe prepared in Example 6 were injected through the tail vein.
  • a 2.0% isoflurane-oxygen mixed gas was used to maintain the anesthesia of the mice.
  • PET/CT scanning Siemens Inveon microPET was performed synchronously after the injection, and images were collected for 1 hour. The results are shown in Figure 1.
  • the circled position is the location of the tumor. It can be clearly seen that the tumor site has a higher enrichment of radioactive signals.
  • the tumor has a good imaging effect from the image, and the signal in the liver site is less than 1% ID/g, which is better than the previous probes.
  • mice Three commercially available SPF-grade Balb/c nude mice were inoculated with A549 cells (human non-small cell lung cancer cells) in the axilla of the left forelimb.
  • A549 cells human non-small cell lung cancer cells
  • 100-150 ⁇ Ci of the M7 probe prepared in Example 7 were injected through the tail vein.
  • the mice were anesthetized with a 2.0% isoflurane-oxygen mixed gas.
  • PET/CT scanning Siemens Inveon microPET was performed synchronously after the injection, and images were collected for 1 hour. The results are shown in Figure 2.
  • the circled position is the location of the tumor. It can be clearly seen that the tumor site has a higher enrichment of radioactive signals.
  • the tumor has a good imaging effect from the image, and the signal in the liver site is less than 2% ID/g, which is better than the previous probes.

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Abstract

L'invention concerne une sonde d'imagerie moléculaire ciblant la poly(ADP-ribose) polymérase, son procédé de préparation et son utilisation. La sonde d'imagerie moléculaire est représentée par la formule Ia ou Ib. Le composé peut être appliqué à une émission de positrons ciblant PARP, à une émission monophotonique ou à des sondes d'imagerie par résonance magnétique nucléaire, et présente une grande perspective d'application dans le traitement d'imagerie de maladies telles que des tumeurs et des anomalies d'expression de PARP.
PCT/CN2024/138338 2023-12-11 2024-12-11 Sonde d'imagerie moléculaire ciblant la poly(adp-ribose) polymérase, son procédé de préparation et son utilisation Pending WO2025124414A1 (fr)

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CN202311692458.3A CN120136843A (zh) 2023-12-11 2023-12-11 一种靶向多聚adp核糖聚合酶的分子影像探针、制备方法及其应用
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Citations (7)

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WO2016033293A1 (fr) * 2014-08-27 2016-03-03 Memorial Sloan Kettering Cancer Center Agents thérapeutiques et de diagnostic ciblés marqués avec un radiohalogénure
CN110997068A (zh) * 2017-05-24 2020-04-10 宾夕法尼亚大学董事会 用于成像和放射疗法的经放射标记的荧光parp抑制剂
CN113813405A (zh) * 2021-09-27 2021-12-21 江西中医药大学 基于赖诺普利的分子影像探针及其应用
CN114014843A (zh) * 2021-11-17 2022-02-08 北京大学第一医院 一种psma靶向核素/荧光双模态配体和分子探针与应用
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