CN116589527B - Granzyme B targeted inhibitor, nuclear medicine probe and application - Google Patents

Granzyme B targeted inhibitor, nuclear medicine probe and application Download PDF

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CN116589527B
CN116589527B CN202310456763.6A CN202310456763A CN116589527B CN 116589527 B CN116589527 B CN 116589527B CN 202310456763 A CN202310456763 A CN 202310456763A CN 116589527 B CN116589527 B CN 116589527B
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granzyme
tumor
nuclear medicine
probe
targeted inhibitor
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CN116589527A (en
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徐红闯
张景明
杨兴
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Peking University First Hospital
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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
    • A61K51/0474—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
    • 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
    • A61K51/0468—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424—Serine endopeptidases (3.4.21)
    • C12N9/6467—Granzymes, e.g. granzyme A (3.4.21.78); granzyme B (3.4.21.79)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
    • C12Y304/21—Serine endopeptidases (3.4.21)
    • C12Y304/21079—Granzyme B (3.4.21.79)

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Abstract

The invention belongs to the field of nuclear medicine, and relates to a granzyme B targeted inhibitor, a nuclear medicine probe and application. The granzyme B targeted inhibitor has a structure shown in a formula I. The inhibitor and the probe have good granzyme B inhibition effect, the probe marked by nuclides is concentrated in a tumor area, has obviously higher tumor uptake, tumor-to-meat ratio and tumor-to-liver ratio than the existing imaging agent, and is a granzyme B targeting molecular probe with great potential.

Description

Granzyme B targeted inhibitor, nuclear medicine probe and application
Technical Field
The invention belongs to the field of nuclear medicine, and particularly relates to a granzyme B targeted inhibitor, a nuclear medicine probe prepared from the granzyme B targeted inhibitor and application thereof.
Background
GRANZYME (GRANZYME) is a serine protease, including A, B, H, K, M, which is believed to be a key mediator of cell death mediated by Cytotoxic T Lymphocytes (CTLs) and Natural Killer (NK) granule exocytosis. Granzyme B mediated apoptosis generally works with perforin, both released from the lysed granules of CTL and NK cells. Under the action of perforin, the target cell membrane is destroyed and pores with an inner diameter of 16-22nm are formed, so that granzyme enters the target cell, and once internalized, granzyme initiates apoptosis through Caspase-dependent and Caspase-independent pathways. Granzyme B, one of the most prominent effector molecules of granzyme, is currently studied mainly on granule-induced apoptosis pathways, emphasizing the response to tumor and virus-infected cells, and is one of the important markers of cell killing.
In recent years granzyme B has gained widespread attention as a biomarker and therapeutic target for various chronic inflammatory and damaging conditions (e.g. atherosclerosis, aortic aneurysm, heat (burn), aging, pathological angiogenesis, dermatitis, asthma and sepsis) as well as tumor models. Among them, granzyme B is thought to play a pathological role in aortic aneurysm progression, being widely distributed in thoracic and abdominal aortic aneurysm tissues of patients compared to normal human aorta, continuous infusion of Ang II for 28 days promoted formation of aortic aneurysms on the kidneys in preclinical mouse models of abdominal aortic aneurysms, and diffuse granzyme B staining was shown in adventitia and thrombus. Diffuse granzyme B staining was associated with increased mortality and rupture of aneurysms in mice. Therefore, early and timely prediction of the correlation of granzyme B with various immune diseases such as aneurysms, organ transplants and the like, and timely establishment of other treatment strategies are of great importance to patients. The presently recommended imaging examinations include multiparameter nuclear magnetism (multiparametric magnetic resonance imaging, mpMRI), computerized tomography (computed tomography, CT). However, the traditional imaging method only provides relevant information of disease morphology, and prognosis cannot be predicted.
The expression quantity of granzyme B is closely related to immune related diseases, so PET imaging of granzyme B can reflect the damage of immune response to tissue repair and tumor cells, and has important value in predicting disease prognosis. Because of the lower tumor uptake and higher non-target organ uptake of existing probes, higher tumor uptake and target-to-target ratio of the targeted GZMB nuclear medicine imaging agents are clinically needed. If it is possible to develop targeted granzyme B nuclide imaging/therapeutic agents with good target affinity and in vivo metabolic capacity, in particular 18 The F-labeled reagent provides more efficient tools for immune related disease monitoring and has wide application prospect.
Disclosure of Invention
The invention aims to provide a novel granzyme B targeting reagent which can be used as a nuclear medicine probe.
In a first aspect, the present invention provides a granzyme B targeted inhibitor having the structure of formula I:
in a second aspect, the invention provides the use of a granzyme B targeted inhibitor as described above in the preparation of a nuclear medicine probe.
In a third aspect the present invention provides a nuclear medicine probe which is a radionuclide labelled granzyme B targeted inhibitor as described above.
According to the invention, the radionuclide may be a diagnostic radionuclide or a therapeutic radionuclide.
Further, the diagnostic radionuclide may be 68 Ga、 64 Cu、 18 F、 86 Y、 90 Y、 89 Zr、 111 I n、 99m Tc、 11 C、 123 I、 125 I and 124 at least one of I.
Further, the therapeutic radionuclide may be 177 Lu、 125 I、 131 I、 211 At、 111 I n、 153 Sm、 186 Re、 188 Re、 67 Cu、 212 Pb、 225 Ac、 213 Bi、 212 Bi and Bi 212 At least one of Pb.
In a fourth aspect, the present invention provides the use of a nuclear medicine probe as described above for the preparation of an imaging diagnostic or therapeutic agent targeting granzyme B.
The inhibitor and the probe have good granzyme B inhibition effect, the probe marked by nuclides is concentrated in a tumor area, has obviously higher tumor uptake, tumor-to-meat ratio and tumor-to-liver ratio than the existing imaging agent, and is a granzyme B targeting molecular probe with great potential.
Drawings
The above and other objects, features and advantages of the present invention will become more apparent by describing in more detail exemplary embodiments thereof with reference to the attached drawings.
FIG. 1 shows the synthesis procedure for G1.
Fig. 2 shows a mass spectrum of G1.
FIG. 3 shows 18 PET map of F-labeled G1 tumor-bearing mice.
FIG. 4 shows 18 F-labeled G1 was injected for 30min of tumor bearing mouse biodistribution.
Detailed Description
Preferred embodiments of the present invention will be described in more detail below. While the preferred embodiments of the present invention are described below, it should be understood that the present invention may be embodied in various forms and should not be limited to the embodiments set forth herein.
Preparation of GZMB targeting ligand
Preparation of G1:
g1 structural formula
The synthesis procedure for G1 is shown in FIG. 1. The amino acid coupling was performed according to standard Fmoc solid phase synthesis.
Overall route for the preparation of G1. Reaction conditions: (a) DMF solution of 20% piperidine, DMF solution of Fmoc- (2S, 5S) -5-amino-1,2,4,5,6,7-hexahydroazepino [3,2,1-Hi ] endo-4-one-2-carboxilic acid, HBTU, HOBt and DIPEA; (b) DMF solution of 20% piperidine, DMF solution of Fmoc-L-isoleucine, HBTU, HOBt and DIPEA; (c) DMF solution of 20% piperidine, N-Fmoc-L-aspartic acid-1-tert-butyl ester, HBTU, HOBt and EIPEA; (d) DMF solution of 20% piperidine, DMF solution of NOTA di-tert-butyl ester, HBTU, HOBt and EIPEA; (e) trifluoroacetic acid, water and triisopropylsilane.
Preparation of G1: resin 1 (0.25 mmol) was taken in a mass in a 10mL solid phase synthesis tube, swollen with 2mL Dichloromethane (DCM) and repeated three times for 5min each, followed by three washes with N, N-Dimethylformamide (DMF) for 5min each. The amino protecting group Fmoc was deprotected using 20% piperidine in DMF (v/v), and the procedure was 2mL of 20% piperidine in DMF for 2 min, 10min, followed by 3-5 washes with 2mL DMF for 2 min each. Fmoc amino acid of 3 times the chemical amount was activated with HBTU of 3.6 times the chemical amount in the presence of DIPEA of 7.2 times the chemical amount relative to the resin (0.02 mmol) and then added to the synthesis tube for reaction for 1 hour with electromagnetic stirring. Dissociation of the ligand from the resin and removal of the tert-butyl ester was accomplished using 5mL of trifluoroacetic acid/triisopropylsilane/water (95:2.5:2.5, v/v/v) with stirring for 2 hours, and the resin was washed with 2mL of trifluoroacetic acid, all filtrates were collected, after removal of the trifluoroacetic acid under reduced pressure, the crude product was reverse prepared by HPLC and lyophilized to give the target ligand G1. The ligand structure was identified by mass spectrometry as shown in figure 2.
Marking and quality control
Marking:
18 f: 1.0mg of the G1 sample bottle was weighed out precisely, dissolved by adding 100. Mu.L of DMSO (dimethyl sulfoxide), and then diluted to a ligand concentration of 10. Mu.g/. Mu.L by adding pure water. 5. Mu.L of ligand solution was placed in a bottle, 20. Mu.L of KHP at 0.5mol/L, 7. Mu.L of AlCl at 20mmol/L were taken 3 Solution and 100. Mu.L 18 F-sodium fluoride is added into a precursor bottle, the precursor bottle is uniformly shaken, then the mixture is placed at room temperature for 5min, 100 mu L of ethanol is added into a reaction bottle, and the mixture is uniformly mixed and then reacted for 10min at 110 ℃. After the reaction, 10mL of water for injection was added for dilution, followed by rinsing with activated Sep-pak VAC C C-18 column, followed by rinsing with 5.0mL of pure water and discarding. The product was collected in a bottle with 0.5mL of 80% ethanol solution, and 5.0mL of physiological saline was added to the system for use. Quality control was analyzed by HPLC.
And (3) quality control:
18 radiochemical purity of F complex was determined using HPLC (high performance liquid chromatography) with mobile phase as aqueous solution containing 20% acetonitrile (containing 0.1% tfa), all complexes having a radiochemical purity greater than 95%.
Imaging of the labeled product
Taking 0.1mL of freshly prepared 18 F labelThe complex (5.6 MBq-7.4 MBq) is injected into a mouse with female MC38 tumor (tumor diameter is about 1 cm) through tail vein, and after 1h, isoflurane is used for anesthesia, small animal PET/CT (SUPER-NOVA, pingshen technology, china) imaging is carried out, and the sketching of SUV (standard uptake value) is carried out on the interested region.
As shown in figure 3 and in table 1, 18 the F-G1 complex can be obviously concentrated in a tumor area, the SUVmax of the tumor is 0.41+/-0.13, the SUVmax of the muscle is 0.06+/-0.01, the SUVmax ratio of the tumor to the muscle is 7.46+/-1.87, the SUVmax ratio of the tumor to the liver is 3.07+/-0.99, 18 F-G1 has obvious advantages in tumor uptake, tumor-to-meat ratio and tumor-to-liver ratio, and is a very potential 18 F labeling GZMB targeting molecular probes.
Table 1 complexes SUVmax values and ratios (mean±sd, n=4) in tumors and muscles
18 F-G1 Tumor(s) Muscle Liver Kidney and kidney Tumor/muscle Tumor/liver Tumor/kidney
Mouse 1 0.44 0.06 0.14 0.90 7.33 3.14 0.49
Mouse 2 0.56 0.07 0.13 0.93 8.00 4.31 0.60
Mouse 3 0.38 0.04 0.13 1.06 9.50 2.92 0.36
Mouse 4 0.25 0.05 0.13 0.93 5.00 1.92 0.27
Mean±SD 0.41±0.13 0.06±0.01 0.13±0.01 0.96±0.07 7.46±1.87 3.07±0.99 0.43±0.15
FIG. 4 is a schematic diagram of a preferred embodiment of the present invention 18 Biodistribution data of F-G1 in tumor-bearing mice, as can be seen from the figure, after 30min of injection, 18 F-G1 is concentrated in tumor area, and has certain uptake in metabolic organs such as small intestine, large intestine and kidney, 18 the uptake of F-G1 in tumors was 2.28.+ -. 1.00, in liver and kidney was 1.13.+ -. 0.31 and 4.26.+ -. 1.17, respectively, whereas the ratios of tumor to blood, tumor to muscle were 2.12.+ -. 1.33, 5.92.+ -. 4.01, respectively. While tumor uptake was significantly lower in the control group, including untreated PBS group and the inhibition group, than in the experimental group, these results indicate, 18 F-G1 has obvious advantages in terms of tumor meat ratio and is very potential 18 F labeling GZMB targeting molecular probes.
The foregoing description of embodiments of the invention has been presented for purposes of illustration and description, and is not intended to be exhaustive or limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the various embodiments described.

Claims (7)

1. A granzyme B targeted inhibitor, wherein the granzyme B targeted inhibitor has a structure according to formula I:
2. use of a granzyme B targeted inhibitor of claim 1 in the preparation of a nuclear medicine probe.
3. A nuclear medicine probe, characterized in that it is a radionuclide-labeled granzyme B-targeted inhibitor according to claim 1.
4. The nuclear medicine probe according to claim 3, wherein the radionuclide is a diagnostic radionuclide or a therapeutic radionuclide.
5. The nuclear medicine probe according to claim 4, wherein the diagnostic radionuclide is 68 Ga、 64 Cu、 18 F、 86 Y、 90 Y、 89 Zr、 111 In、 99m Tc、 11 C、 123 I、 125 I and 124 at least one of I.
6. The nuclear medicine probe according to claim 4, wherein the therapeutic radionuclide is 177 Lu、 125 I、 131 I、 211 At、 111 In、 153 Sm、 186 Re、 188 Re、 67 Cu、 212 Pb、 225 Ac、 213 Bi、 212 Bi and Bi 212 At least one of Pb.
7. Use of a nuclear medicine probe according to any one of claims 3 to 6 for the preparation of an imaging diagnostic or therapeutic agent targeting granzyme B.
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CN118388584B (en) * 2024-06-25 2024-08-16 中国医学科学院阜外医院 Granzyme B targeting molecule rotor fluorescent probe and application

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CN113512090A (en) * 2021-04-30 2021-10-19 复旦大学附属肿瘤医院 Granzyme B binding compound, precursor compound thereof and application
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