CN114315795B - 68 Ga-marked inhibitor radioactive probe for targeting fibroblast activation protein and preparation method thereof - Google Patents

68 Ga-marked inhibitor radioactive probe for targeting fibroblast activation protein and preparation method thereof Download PDF

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CN114315795B
CN114315795B CN202111437982.7A CN202111437982A CN114315795B CN 114315795 B CN114315795 B CN 114315795B CN 202111437982 A CN202111437982 A CN 202111437982A CN 114315795 B CN114315795 B CN 114315795B
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fibroblast activation
hbed
activation protein
inhibitor
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CN114315795A (en
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朱霖
洪海燕
查志豪
赵睿玥
孔繁渊
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Beijing Normal University
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Abstract

The present invention relates to a kind of 68 Ga-labeled inhibitor radioactive probe of targeted fibroblast activation protein and a preparation method thereof, belonging to the technical field of radiopharmaceuticals chemistry; the structural formula of the radioactive probe is as follows:
Figure DDA0003382433330000011
the radioactive probe of the invention has the marking time of 5 minutes, the radiochemical yield of more than 99 percent, and the radiochemical purity of the product measured by radio-HPLC of more than 99 percent, and the product shows high affinity and high specificity to fibroblast activation protein, has high in-vitro cell uptake value, and is a more potential fibroblast activation protein PET imaging agent.

Description

68 Ga-marked inhibitor radioactive probe for targeting fibroblast activation protein and preparation method thereof
Technical Field
The present invention relates to 68 Ga-labeled inhibitor-based radioactive probes targeting fibroblast activation protein (Fibroblast activation protein, FAP) ([ the same.) 68 Ga]Ga-HBED-CC-04-DiF-Monomer、 [ 68 Ga]Ga-HBED-CC-04-DiF-Dimer) and a preparation method thereof, belonging to the technical field of radiopharmacy.
Background
Tumor mass consists of tumor cells and tumor interstitials, which account for more than 90% of tumor mass in highly connective tissue-promoting tumors such as breast, colon and pancreatic cancers. Cancer-associated fibroblasts (CAFs), also known as tumor-associated fibroblasts (TAFs) or activated fibroblasts, are an important component of the tumor stroma, involved in the growth, migration and development of tumors. CAFs express different markers such as fibroblast activation protein (fibroblast activation protein, FAP), alpha-smooth muscle actin (alpha-smooth muscle actin, alpha-SMA), vimentin (vimentin), and the like.
Since α -SMA and vimentin are expressed in resting fibroblasts, pericytes and vascular smooth muscle cells, whereas FAP is highly specifically expressed only in activated fibroblasts and not in benign tumors or normal adult tissues, FAP is the most potent molecular marker of CAFs. In addition, FAP is an indispensable factor for promoting proliferation and metastasis of tumor cells, remodelling extracellular matrix, inducing neovascularization, mediating immunosuppression, participating in energy metabolism of tumor cells, and the like. Therefore, FAP becomes a potential target point for tumor imaging and treatment, and further, the deep research of FAP has great significance for diagnosis, treatment and prognosis judgment of malignant tumors.
Notably, activated fibroblasts are present not only in tumors, but also in wound healing and matrix remodeling diseases such as chronic inflammation, myocardial infarction and liver, lung or kidney fibrosis, and therefore FAP is highly expressed not only in tumor interstitial CAFs, but also in many tissue remodeling processes. Therefore, FAP expression is not tumor specific. At the same time, however, FAP-targeted radiopharmaceuticals are applicable not only in tumor imaging and therapy, but also in imaging of many non-tumor diseases such as myocardial infarction, chronic inflammatory diseases, and pulmonary, hepatic, or renal fibrosis.
FAP is a 97kDa type II transmembrane protein that is active only when it exists as a 170kDa dimer (FAP-FAP). The FAP targeted inhibitor radiopharmaceuticals are widely studied and reported for tumor imaging and treatment, and are the research hot spot in recent years.
Loktev et al reported 2018 [ 68 Ga]Ga-FAPI-02。[ 68 Ga]Ga-FAPI-02 exhibits high FAP specificity and binding affinity, both in vitro and in vivo, and is rapidly taken up and internalized by FAP-highly expressing cells. In patients with breast cancer metastasis, lung cancer metastasis, pancreatic cancer metastasis [ in vivo ] 68 Ga]Ga-FAPI-02 is rapidly cleared, mainly by renal excretion, in the normal groupThe tissue uptake was low, and a large accumulation of radioactivity was observed in the primary tumor, lymph node and bone metastasis, and the contrast of the obtained image was high. Comparison [ 68 Ga]Ga-FAPI-02 [ 18 F]Imaging of FDG in patients with locally advanced lung adenocarcinoma, findings 68 Ga]Ga-FAPI-02 is superior to [ 18 F]FDG：[ 68 Ga]The Ga-FAPI-02 has higher uptake in a transfer range, lower background, higher focus contrast and better visibility; and [ with ] 18 F]Strong uptake of FDG in high glucose metabolizing tissues like the brain is different [ 68 Ga]Ga-FAPI-02 selectively targets FAP-highly expressed tissues. Although [ although ] 68 Ga]Ga-FAPI-02 shows preliminary good tumor imaging properties, but its rapid clearance rate may not reflect well the situation of tumors such as head and neck cancer, ovarian cancer and liver cancer, and in addition, short tumor residence time is not suitable for treatment, so FAP targeted inhibitor radiopharmaceuticals with longer tumor residence time need to be developed.
For this purpose, lindner et al reported FAPI-04 in the same year and applied to 68 Ga and 177 labeling of Lu. [ 68 Ga]Ga-FAPI-04 shows a sum [ 68 Ga]Ga-FAPI-02 has similar rapid renal clearance, low background and high tumor uptake. Use by researchers 177 Lu marks FAPI-04 to obtain [ 177 Lu]The biological distribution experimental result of Lu-FAPI-04 and HT1080-FAP tumor-bearing mice shows that [ 177 Lu]Lu-FAPI-04 ratio 177 Lu]Lu-FAPI-02 had higher tumor uptake and longer tumor retention, and both had very low background, after 24 hours [ 177 Lu]Effective tumor uptake ratio of Lu-FAPI-04 [ 177 Lu]Lu-FAPI-02 was 100% higher, suggesting that FAPI-04 has therapeutic potential. In one patient [ use 90 Y]Treatment with Y-FAPI-04 showed a significant reduction in pain in patients, with metastasis and low background observed for 24 hours, no side effects such as hematological toxicity were observed, but limited clinical data, and still required more clinical trials to verify feasibility.
To further increase tumor uptake and tumor residence time, loktev et al reported FAPI-21 and in 2019FAPI-46.HT1080-FAP tumor-bearing mice biodistribution results showed [ 68 Ga]Ga-FAPI-21 [ 68 Ga]Ga-FAPI-46 tumor uptake was higher than [ 68 Ga]Ga-FAPI-04, but [ 68 Ga]Liver and muscle uptake of Ga-FAPI-21 is higher than [ 68 Ga]Ga-FAPI-04；[ 68 Ga]Ga-FAPI-46 has a higher tumor/blood, tumor/muscle and tumor/liver ratio than [ 68 Ga]Ga-FAPI-04 and [ 68 Ga]Ga-FAPI-21。[ 177 Lu]Lu-FAPI-21 and [ 177 Lu]Lu-FAPI-46 had a tumor accumulation higher than [ 1-4 hours after injection 177 Lu]Lu-FAPI-04; tumor retention 24 hours after injection [ 177 Lu]Lu-FAPI-21>[ 177 Lu]Lu-FAPI-04>[ 177 Lu]Lu-FAPI-46; the blood radioactivity levels of the three compounds were comparable [ 177 Lu]The tumor/liver, tumor/kidney and tumor/brain ratios of Lu-FAPI-46 were increased. Intravenous injection in patients with epidermoid mucous, oropharyngeal, ovarian and colorectal cancers 68 Ga]Ga-FAPI-21 [ 68 Ga]Ga-FAPI-46, both of which accumulate rapidly in primary tumors and metastases, SUVmax is 11.9+ -3.33 and 12.76+ -0.90 after 1 hour of administration, normal tissue has low radioactive uptake, radioactivity is rapidly cleared from blood, and is mainly excreted through kidneys; but observe [ 68 Ga]Increased uptake of Ga-FAPI-21 in the oral mucosa, thyroid, parotid and submaxillary glands suggests that FAPI-21 may not be suitable as a therapeutic agent. Notably, tumor accumulation is highly dependent on tumor type. Lindner et al found injection 68 Ga]Ga-FAPI-21 or [ 68 Ga]After Ga-FAPI-46, the radioactivity of the tumor remained relatively stable in colorectal, ovarian, oropharyngeal and pancreatic cancers, while in breast cancer the radioactivity of the tumor continued to decrease within 3 hours; in addition, tumor uptake was continuously increased in one patient with a primary tumor, 1-3 hours after administration.
Human tumors form complex heterogeneous structures, the number and distribution of FAP-expressing CAFs and the number of FAP molecules per cell may be different, resulting in radiopharmaceuticals with different pharmacokinetic properties at different tumor types. In clinical studies, we observed [ [ 68 Ga]Ga-FAPI-21 orPerson [ 68 Ga]Uptake differences of Ga-FAPI-46 in different types of tumors: uptake in colorectal, ovarian, oropharyngeal and pancreatic cancers is relatively stable, while uptake in breast cancer continues to decline. This may be caused by heterogeneous sources of CAFs. Due toOrigin of originThese CAFs may exhibit different proteomes, have strong variation, and even lack FAP expression. Thus, radiopharmaceuticals with longer tumor residence times may reflect the reality of the tumor better than those that clear rapidly. In addition, radiopharmaceuticals with longer tumor residence times and high tumor uptake are also clinically desirable for therapeutic agents. Currently, the most successful FAP-targeted inhibitor imaging drugs are FAPI-02, FAPI-04 and FAPI-46, and they 68 Ga-labeled drugs are most used clinically, but there is still room for improvement to achieve longer tumor residence times.
Therefore, the novel inhibitor radioactive probe can show high affinity and high specificity to fibroblast activation protein, has better tumor uptake and longer tumor residence time, and becomes a technical problem which needs to be solved in the technical field.
Disclosure of Invention
One of the objects of the present invention is to provide 68 Ga-labeled inhibitor radioactive probes for targeting fibroblast activation protein (Fibroblast activation protein, FAP), which show high affinity and high specificity for the fibroblast activation protein, have better tumor uptake and longer tumor residence time, and are more potential FAP/PET imaging agents.
The above object of the present invention is achieved by the following technical solutions:
68 ga-labeled inhibitor radioactive probe targeting fibroblast activation protein has a structural formula shown in figure 6.
It is another object of the present invention to provide the above 68 A preparation method of Ga-marked inhibitor radioactive probe of targeting fibroblast activating protein.
The above object of the present invention is achieved by the following technical solutions:
68 the preparation method of the Ga-marked inhibitor radioactive probe for targeting fibroblast activation protein comprises the following steps: condensing the bifunctional linker HBED-CC and fibroblast activation protein inhibitor in the presence of alkali and condensing agent, removing protecting group with acid, dissolving the obtained product in dimethyl sulfoxide, adding 68 Ga]GaCl 3 Mixing the above solutions, and heating to obtain the above structural formula 68 Ga-labeled inhibitor-type radioactive probes targeting fibroblast activation proteins.
The reaction scheme is shown in FIG. 7.
Preferably, the base is N, N-diisopropylethylamine added in an amount of 3 to 5 equivalents; the condensing agent is 1-hydroxybenzotriazole and 1-ethyl- (3-dimethylaminopropyl) carbodiimide, and the addition amounts are 1 equivalent; the fibroblast activation protein inhibitor is (S) -N- (2- (2-cyano-4, 4-difluoro pyrrolidin-1-yl) -2-ethoxy) -6- (3- (piperazine-1-yl) propoxy) quinoline-4-carboxamide, and the addition amount is 1-5 equivalents; the acid was trifluoroacetic acid and the amount added was 3 ml.
Preferably, the method comprises the steps of, 68 the preparation method of the Ga-marked inhibitor radioactive probe for targeting fibroblast activation protein comprises the following specific steps:
step 1: 68 synthesis of Ga-labeled precursor of inhibitor-type radioactive probe targeting fibroblast activation protein
Dissolving (S) -N- (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-ethoxy) -6- (3- (piperazin-1-yl) propoxy) quinoline-4-carboxamide in anhydrous dimethylformamide, adding 1-hydroxybenzotriazole, N-diisopropylethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide and 3,3' - (((2,2,13,13-tetramethyl-4, 11-dioxo-3, 12-dioxa-6, 9-diazatetradecane-6, 9-diyl) bis (methylene)) bis (4-hydroxy-3, 1-phenyl)) dipropionic acid to the mixed solution, reacting at room temperature, adding ethyl acetate and saturated brine to the mixed solution after overnight, washing, and collecting an organic phase filtrate; the organic phase filtrate is dried with anhydrous sodium sulfate, filtered, and solid impurities are removed; removing solvent in the filtrate by rotary evaporator under reduced pressure, separating with silica gel column with mixed solution of dichloromethane, methanol and 25% ammonia water (4/1/0.1, v/v/v), collecting components, rotary evaporator and oil pump under reduced pressure, removing solvent to obtain brown yellow oily substance, dissolving the brown yellow oily substance in trifluoroacetic acid, stirring at room temperature, removing solvent by rotary evaporator and oil pump under reduced pressure, recrystallizing with diethyl ether to obtain brown yellow solid; dissolving the obtained brown yellow solid in dimethyl sulfoxide, and purifying by Semi-HPLC to obtain brown yellow solid HBED-CC-04-DiF-Monomer;
step 2: 68 labeling of Ga-labeled inhibitor-based radioactive probes targeting fibroblast activation protein
Dissolving HBED-CC-04-DiF-Monomer (labeled precursor) obtained in step 1 in dimethyl sulfoxide, adding sodium acetate solution to obtain labeled precursor sodium acetate solution, eluting germanium gallium generator (iThemba laboratories,740MBq,20 mCi) with high-purity hydrochloric acid solution, and collecting the product 68 Ga]GaCl 3 Adding hydrochloric acid solution into labeled precursor sodium acetate solution, mixing, reacting at 95deg.C, cooling to room temperature, and detecting with a radioactivity detector (Flow-Count, eckert)&Ziegler) high performance liquid chromatography (radio-HPLC, agilent 1260Infinity II system) in mobile phase of 0.1% aqueous trifluoroacetic acid (v/v) and 0.1% acetonitrile trifluoroacetic acid (v/v) to give a radiochemical yield of greater than 99% 68 Ga]Ga-HBED-CC-04-DiF-Monomer。
Preferably, in step 2, the test conditions of the high performance liquid chromatography with the radioactivity detector are: the first mobile phase is 0.1% trifluoroacetic acid aqueous solution (v/v), the second mobile phase is 0.1% trifluoroacetic acid acetonitrile solution (v/v), and the gradient elution conditions are: 0-10 minutes, 100% -35% of a first mobile phase; 10-12 minutes, 35% -100% of the first mobile phase; 12-15 minutes, 100% of the first mobile phase; the flow rate of the mobile phase was 1 ml/min.
Preferably, the method comprises the steps of, 68 the preparation method of the Ga-marked inhibitor radioactive probe for targeting fibroblast activation protein comprises the following specific steps:
step 1: 68 synthesis of Ga-labeled precursor of inhibitor-type radioactive probe targeting fibroblast activation protein
Dissolving (S) -N- (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-ethoxy) -6- (3- (piperazin-1-yl) propoxy) quinoline-4-carboxamide in anhydrous dimethylformamide, adding 1-hydroxybenzotriazole, N-diisopropylethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide and 3,3' - (((2,2,13,13-tetramethyl-4, 11-dioxo-3, 12-dioxa-6, 9-diazatetradecane-6, 9-diyl) bis (methylene)) bis (4-hydroxy-3, 1-phenyl)) dipropionic acid to the mixed solution, reacting at room temperature, adding ethyl acetate and saturated brine to the mixed solution for washing after overnight, and collecting an organic phase filtrate; the organic phase filtrate is dried with anhydrous sodium sulfate, filtered, and solid impurities are removed; removing solvent in the filtrate by rotary evaporator under reduced pressure, separating with silica gel column with mixed solution of dichloromethane, methanol and 25% ammonia water (20/1/0.1, v/v/v), collecting components, rotary evaporator and oil pump under reduced pressure, removing solvent to obtain brown red oily substance, dissolving the obtained brown red oily substance in trifluoroacetic acid, stirring at room temperature, removing solvent by rotary evaporator and oil pump under reduced pressure, recrystallizing with diethyl ether to obtain brown red solid; dissolving the obtained brown solid in dimethyl sulfoxide, and purifying by Semi-HPLC to obtain brown solid HBED-CC-04-DiF-Dimer;
step 2: 68 labeling of Ga-labeled inhibitor-based radioactive probes targeting fibroblast activation protein
Dissolving HBED-CC-04-DiF-Dimer (labeled precursor) in dimethyl sulfoxide, adding sodium acetate solution to obtain labeled precursor sodium acetate solution, eluting germanium gallium generator (iThemba laboratories,740MBq,20 mCi) with high-purity hydrochloric acid solution, and collecting the product 68 Ga]GaCl 3 Adding hydrochloric acid solution into labeled precursor sodium acetate solution, mixing, reacting at 95deg.C, cooling to room temperature, and detecting with a radioactivity detector (Flow-Count, eckert)&High performance liquid chromatography (radio-HPLC, agilent 1260Infinity II system) in Ziegler) and measuring its labeling in mobile phase of 0.1% aqueous trifluoroacetic acid (v/v) and 0.1% acetonitrile trifluoroacetic acid (v/v)Yield, yield of radiochemistry greater than 99% 68 Ga]Ga-HBED-CC-04-DiF-Dimer。
Preferably, in step 2, the test conditions of the high performance liquid chromatography with the radioactivity detector are: the first mobile phase is 0.1% trifluoroacetic acid aqueous solution (v/v), the second mobile phase is 0.1% trifluoroacetic acid acetonitrile solution (v/v), and the gradient elution conditions are: 0-10 minutes, 100% -35% of a first mobile phase; 10-12 minutes, 35% -100% of the first mobile phase; 12-15 minutes, 100% of the first mobile phase; the flow rate of the mobile phase was 1 ml/min.
The beneficial effects are that:
the invention is characterized in that 68 Ga-labeled inhibitor radioactive probes for targeting fibroblast activation protein show high affinity and high specificity for the fibroblast activation protein, have better tumor uptake and longer tumor residence time, and are more potential FAP/PET imaging agents.
The invention is further illustrated by the drawings and the detailed description which follow, but are not meant to limit the scope of the invention.
Drawings
FIG. 1 is a block diagram of the present invention [ preparation of example 1 ] 68 Ga]Radioactive HPLC profile of Ga-HBED-CC-04-DiF-Monomer labeling reaction solution.
FIG. 2 is a diagram of [ preparation in example 2 ] of the present invention 68 Ga]Radioactive HPLC profile of Ga-HBED-CC-04-DiF-Dimer labeling reaction solution.
FIG. 3 shows the in vitro HT1080-FAP cell uptake [ in application example 1 ] of the present invention 68 Ga]Ga-HBED-CC-04-DiF-Monomer and [ 68 Ga]Intake vs. time graph of Ga-HBED-CC-04-DiF-Dimer.
FIG. 4 shows an in vitro HT1080-FAP cell uptake assay of application example 1 of the present invention [ 68 Ga]Ga-HBED-CC-04-DiF-Monomer and [ 68 Ga]Specific binding pattern of Ga-HBED-CC-04-DiF-Dimer to fibroblast activation protein.
FIG. 5 is a graph showing the binding affinity of HBED-CC-04-DiF-Monomer and HBED-CC-04-DiF-Dimer to fibroblast activation protein in the IC50 value assay of application example 2 of the present invention.
FIG. 6 shows the present invention 68 Structural formula of Ga-marked inhibitor radioactive probe targeting fibroblast activating protein.
FIG. 7 shows the present invention 68 Reactive formulation of Ga-labeled inhibitor-type radioactive probes targeting fibroblast activation protein.
FIG. 8 is a synthetic reaction equation of HBED-CC-04-DiF-Monomer in step (1) of application example 1 of the present invention.
FIG. 9 shows the procedure (2) of the present invention in practical example 1 68 Ga]Ga-HBED-CC-04-DiF-Monomer.
FIG. 10 shows the synthesis reaction equation of HBED-CC-04-DiF-Dimer in step (1) of application example 2 of the present invention.
FIG. 11 shows the procedure (2) in application example 2 of the present invention 68 Ga]Ga-HBED-CC-04-DiF-Dimer.
The specific embodiment is as follows:
unless otherwise specified, reagents and raw materials used in the preparation methods and the detection methods described in the following examples and comparative examples are commercially available, and the equipment used is common equipment.
The concentrations and ratios described in the following examples and comparative examples are in weight units unless otherwise specified.
Example 1 ([ V ]) 68 Ga]Ga-HBED-CC-04-DiF-Monomer)
Step 1: 68 synthesis of Ga-labeled precursor of inhibitor-type radioactive probe targeting fibroblast activation protein
The synthetic reaction equation for (S) -3- (5-methyl- ((3-carboxymethyl) (2- ((3-carboxymethyl) (3- (4- (4- (4- (2- (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-oxoethyl) carbamoyl) quinolin-7-yl) -4-oxopropyl) piperazin-1-yl) -3-oxopropyl) -2-hydroxybenzyl) amino) ethyl) amino) -4-hydroxyphenyl) propionic acid, which is HBED-CC-04-DiF-Monomer, is shown in FIG. 8.
The synthesis method comprises the following steps:
(S) -N- (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-ethoxy) -6- (3- (piperazin-1-yl) propoxy) quinoline-4-carboxamide (52 mg, 0.1 mmol) was dissolved in 2 ml of anhydrous dimethylformamide, 1-hydroxybenzotriazole (17 mg, 0.1 mmol), N-diisopropylethylamine (68 mg, 0.5 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide (25 mg, 0.1 mmol) and 3,3' - (((2,2,13,13-tetramethyl-4, 11-dioxo-3, 12-dioxa-6, 9-diazatetradecane-6, 9-diyl) bis (methylene)) bis (4-hydroxy-3, 1-phenyl)) dipropionic acid (57 mg, 0.1 mmol) were added to the mixed solution, reacted overnight at room temperature, after which 30 ml of ethyl acetate and 10 ml were added to the mixed solution, and the saturated organic phase was washed twice; the organic phase filtrate is dried with anhydrous sodium sulfate, filtered, and solid impurities are removed; removing organic solvent in the filtrate by using a rotary evaporator, separating by using a silica gel column (refined column chromatography silica gel, 200-300 meshes) by using dichloromethane/methanol/25% ammonia water (4/1/0.1, v/v/v), collecting components, removing the organic solvent in the components by using the rotary evaporator and an oil pump to obtain brown yellow oily matter, dissolving the obtained brown yellow oily matter in 3 ml of trifluoroacetic acid, stirring for 7 hours at room temperature, removing the solvent by using the rotary evaporator and the oil pump, and recrystallizing by using diethyl ether to obtain brown yellow solid; the resulting brown-yellow solid was dissolved in dimethyl sulfoxide and purified by Semi-HPLC (0.1% trifluoroacetic acid/acetonitrile=7/3, v/v) to give 16 mg (yield: 20%) of HBED-CC-04-DiF-Monomer as a brown-yellow solid;
confirmation of Compound HBED-CC-04-DiF-Monomer:
1 H NMR(600MHz,DMSO)δ8.91-8.85(m,1H),8.05(dd,J＝9.2,2.0Hz,1H), 7.89(s,1H),7.66-7.59(m,1H),7.55-7.51(m,1H),7.07(t,J＝7.7Hz,4H),6.80(d,J ＝8.2Hz,2H),5.11(d,J＝7.4Hz,1H),4.45-4.35(m,2H),4.34-4.16(m,8H),4.16- 3.96(m,10H),3.33-3.28(m,2H),3.23-3.21(m,4H),2.95-2.80(m,2H),2.69(t,J＝ 7.3Hz,4H),2.60(d,J＝8.3Hz,2H),2.26-2.17(m,2H).
HRMS (ESI) theoretical molecular weight C 50 H 58 F 2 N 8 O 12 [M+H] + 1001.4221 measured molecular weight 1001.4239[ M+H ]] + ；
Step 2: 68 ga labelingIs targeted to fibroblast activation protein
[ 68 Ga]The labelling reaction equation for Ga-HBED-CC-04-DiF-Monomer is shown in FIG. 9.
The marking method comprises the following steps:
8 micrograms of the labeled precursor HBED-CC-04-DiF-Monomer was dissolved in 80 microliters of dimethyl sulfoxide, and 135 microliters of sodium acetate buffer with a concentration of 3 moles/liter was added to obtain a labeled precursor sodium acetate buffer; the gallium germanium generator ((iThemba laboratories,740MBq,20 mCi) was rinsed with 6 ml of a highly pure 0.6 mol/l hydrochloric acid solution to give [ 68 Ga]GaCl 3 0.3 ml of the solution was taken and added to a sodium acetate buffer as a precursor for labeling, followed by mixing, reacting at 95℃for 5 minutes, cooling to room temperature, and detecting with a radioactivity detector (Flow-Count, eckert&Ziegler) high performance liquid chromatography (radio-HPLC, agilent 1260Infinity II system) in mobile phase of 0.1% aqueous trifluoroacetic acid (v/v) and 0.1% acetonitrile trifluoroacetic acid (v/v) gave a radiochemical yield of 99.56% 68 Ga]Ga-HBED-CC-04-DiF-Monomer；
As shown in FIG. 1, it is prepared in example 1 of the present invention 68 Ga]Radioactive HPLC spectrum of Ga-HBED-CC-04-DiF-Monomer labeling reaction liquid, and spectrum display 68 Ga]The radiochemical purity of Ga-HBED-CC-04-DiF-Monomer is more than 99 percent;
in the radio-HPLC assay described in the above step, the first mobile phase is 0.1% aqueous trifluoroacetic acid (v/v), the second mobile phase is 0.1% acetonitrile trifluoroacetic acid (v/v), and the gradient elution conditions are: 0-10 minutes, 100% -35% of a first mobile phase; 10-12 minutes, 35% -100% of the first mobile phase; 12-15 minutes, 100% of the first mobile phase; the flow rate of the mobile phase was 1 ml/min.
Example 2 ([ V ]) 68 Ga]Ga-HBED-CC-04-DiF-Dimer)
Step 1: 68 synthesis of Ga-labeled precursor of inhibitor-type radioactive probe targeting fibroblast activation protein
The synthesis reaction equation for HBED-CC-04-DiF-Dimer, i.e., 2' - (ethane-1, 2-diylbis (5- (3- (4- (4- (4- (2- ((S) -2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-oxoethyl) carbamoyl) quinolin-7-yl) -4-oxopropyl) piperazin-1-yl) -3-oxopropyl) -2-hydroxybenzyl)) azetidine, is shown in FIG. 10.
The synthesis method comprises the following steps:
(S) -N- (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-ethoxy) -6- (3- (piperazin-1-yl) propoxy) quinoline-4-carboxamide (100 mg, 0.2 mmol) was dissolved in 2 ml of anhydrous dimethylformamide, 1-hydroxybenzotriazole (23 mg, 0.2 mmol), N-diisopropylethylamine (84 mg, 0.6 mmol), 1-ethyl- (3-dimethylaminopropyl) carbodiimide (32 mg, 0.2 mmol) and 3,3' - (((2,2,13,13-tetramethyl-4, 11-dioxo-3, 12-dioxa-6, 9-diazatetradecane-6, 9-diyl) bis (methylene)) bis (4-hydroxy-3, 1-phenyl)) dipropionic acid (23 mg, 0.04 mmol) were added to the mixed solution, after reaction at room temperature, 30 ml of ethyl acetate and 10 ml were added to the mixed solution overnight, and the saturated brine was washed, and the organic phase was collected; the organic phase filtrate is dried with anhydrous sodium sulfate, filtered, and solid impurities are removed; removing solvent in the filtrate under reduced pressure by using a rotary evaporator, separating by using a silica gel column (refined column chromatography silica gel, 200-300 meshes) by using dichloromethane/methanol/25% ammonia water (20/1/0.1, v/v/v), collecting components, removing organic solvent in the components by using the rotary evaporator and an oil pump to obtain a brown-red oily substance, dissolving the obtained brown-red oily substance in 3 ml of trifluoroacetic acid, stirring at room temperature for 7 hours, removing the solvent by using the rotary evaporator and the oil pump, and recrystallizing by using diethyl ether to obtain a brown-red solid; the resulting brown solid was dissolved in dimethyl sulfoxide and purified by Semi-HPLC (0.1% trifluoroacetic acid/acetonitrile=7/3, v/v) to give 20 mg (yield: 40%) of brown solid HBED-CC-04-DiF-Monomer;
confirmation of the Compound HBED-CC-04-DiF-Dimer:
1 H NMR(600MHz,DMSO)δ8.84(d,J＝4.3Hz,2H),8.03(d,J＝9.2Hz,2H), 7.88(d,J＝2.2Hz,2H),7.56(d,J＝4.2Hz,2H),7.48(dd,J＝9.2,1.5Hz,2H),7.13- 7.06(m,4H),6.80(d,J＝8.0Hz,2H),5.13(dd,J＝9.2,2.3Hz,2H),4.28-4.18(m, 12H),4.02-3.99(m,4H),3.66-3.63(m,8H),3.34-3.31(m,10H),3.21-3.19(m,6H), 2.98-2.76(m,6H),2.72-2.69(m,4H),2.62-2.59(m,4H),2.25-2.20(m,4H).
HRMS (ESI) theoretical molecular weight C 74 H 84 F 4 N 14 O 14 [M+H] + 1469.6306 measured molecular weight 1469.6306[ M+H ]] + ；
Step 2: 68 labeling of Ga-labeled inhibitor-based radioactive probes targeting fibroblast activation protein
[ 68 Ga]The labelling reaction equation for Ga-HBED-CC-04-DiF-Dimer is shown in FIG. 11.
The marking method comprises the following steps:
12. Mu.g of the labeled precursor HBED-CC-04-DiF-Dimer was dissolved in 120. Mu.l of dimethyl sulfoxide, and 135. Mu.l of 3 mol/l sodium acetate buffer was added to obtain a precursor solution; the gallium germanium generator (iThemba laboratories,740MBq,20 mCi) was rinsed with 6 ml of a highly pure 0.6 mol/l hydrochloric acid solution, and the resulting [ 68 Ga]GaCl 3 0.3 ml of the solution was added to the precursor solution, and the mixture was mixed well, reacted at 95℃for 5 minutes, cooled to room temperature, and detected by a detector with radioactivity (Flow-Count, eckert)&Ziegler) high performance liquid chromatography (radio-HPLC, agilent 1260Infinity II system) in mobile phase of 0.1% aqueous trifluoroacetic acid (v/v) and 0.1% acetonitrile trifluoroacetic acid (v/v) gave a radiochemical yield of 99.89% 68 Ga]Ga-HBED-CC-04-DiF-Dimer；
As shown in FIG. 2, it is [ produced in example 2 of the present invention ] 68 Ga]Radioactive HPLC pattern of Ga-HBED-CC-04-DiF-Dimer labeling reaction liquid, pattern display 68 Ga]The radiochemical purity of Ga-HBED-CC-04-DiF-Dimer is more than 99 percent;
in the radio-HPLC assay described in the above step, the first mobile phase is 0.1% aqueous trifluoroacetic acid (v/v), the second mobile phase is 0.1% acetonitrile trifluoroacetic acid (v/v), and the gradient elution conditions are: 0-10 minutes, 100% -35% of a first mobile phase; 10-12 minutes, 35% -100% of the first mobile phase; 12-15 minutes, 100% of the first mobile phase; the flow rate of the mobile phase was 1 ml/min.
Application example 1
[ 68 Ga]Ga-HBED-CC-04-DiF-Monomer and [ 68 Ga]In vitro cellular uptake of Ga-HBED-CC-04-DiF-Dimer
(1) HT1080-FAP (FAP positive) cells (. About.5X10) 5 Well) were inoculated in 6-well plates, cultured in an incubator for 60 hours with a cell coverage of 90-100%; after 60 hours, the culture was aspirated, the cells were washed twice with phosphate buffered saline, and 12. Mu. Ci was added to the well plate [ 68 Ga]Ga-HBED-CC-04-DiF-Monomer or [ 68 Ga]Ga-HBED-CC-04-DiF-Dimer or [ 68 Ga]Ga-FAPI-04, incubated at 37℃for 10, 30, 60, 90 and 120 minutes, cell uptake was blocked at 60 minutes using 10. Mu.M UAMC-1110 (FAP inhibitor), after incubation was completed, the solution was aspirated, the cells were rapidly washed three times with phosphate buffered saline, and cell uptake was stopped; all cells are lysed by sodium hydroxide, and the lysate is collected for radioactive counting;
(2) From the results of in vitro cell uptake experiments, it can be seen that: [ 68 Ga]Ga-HBED-CC-04-DiF-Monomer and [ 68 Ga]Ga-HBED-CC-04-DiF-Dimer uptake in HT1080-FAP (FAP positive) cells in vitro is high, increasing with time, 10 minutes uptake is higher than [ 68 Ga]Maximum uptake of Ga-FAPI-04, 120 min uptake>60%) are all significantly higher than [ 68 Ga]Ga-FAPI-04; after adding fibroblast activation protein inhibitor UAMC-1110, both were blocked from uptake, indicating that 68 Ga]Ga-HBED-CC-04-DiF-Monomer and [ 68 Ga]Ga-HBED-CC-04-DiF-Dimer specifically binds to fibroblast activation protein.
As shown in FIG. 3, in vitro HT1080-FAP cell uptake [ in application example 1 ] of the present invention 68 Ga]Ga-HBED-CC-04-DiF-Monomer and [ 68 Ga]Intake-time graph of Ga-HBED-CC-04-DiF-Dimer, n=3.
As shown in FIG. 4, in vitro HT1080-FAP cell uptake assay analysis in application example 1 of the present invention 68 Ga]Ga-HBED-CC-04-DiF-Monomer and [ 68 Ga]Specific binding pattern of Ga-HBED-CC-04-DiF-Dimer to fibroblast activation protein, n=3, significant difference in cell uptake between the non-added UAMC1110 group and the added UAMC1110 groupAnd (3) displaying: [ 68 Ga]Ga-HBED-CC-04-DiF-Monomer and [ 68 Ga]Ga-HBED-CC-04-DiF-Dimer specifically binds to fibroblast activation protein.
Application example 2
IC50 value determination of HBED-CC-04-DiF-Monomer and HBED-CC-04-DiF-Dimer
(1) HT1080-FAP (FAP positive) cells (. About.5X10) 5 Well) was inoculated into a 6-well plate, cultured in an incubator for 60 hours with a cell coverage of 90 to 100%, after 60 hours, the culture solution was aspirated, the cells were washed twice with a phosphate buffer solution, and 12. Mu. Ci was added to the plate [ 68 Ga]Ga-FAPI-04 and HBED-CC-04-DiF-Monomer or HBED-CC-04-DiF-Dimer or FAPI-04, so that the final concentration of HBED-CC-04-DiF-Monomer or HBED-CC-04-DiF-Dimer or FAPI-04, respectively, is 10 -9.5 、10 -9 、10 -8.5 、10 -8 、10 -7 And 10 -6 After incubation at 37 ℃ for 60 minutes, the solution was aspirated, the cells were rapidly washed three times with phosphate buffered saline, cell uptake was stopped, all cells were lysed with sodium hydroxide, and the lysates were collected for radioenumeration;
as shown in fig. 5, for the experimental analysis of IC50 value determination in application example 2 of the present invention, HBED-CC-04-DiF-Monomer and HBED-CC-04-DiF-oligomer binding affinity patterns with fibroblast activation protein, the IC50 values of n=3, nm scale showed: the binding affinity of the HBED-CC-04-DiF-Monomer and the HBED-CC-04-DiF-Dimer to fibroblast activation protein is high;
(2) From the IC50 value measurement experiment results, it can be seen that: HBED-CC-04-DiF-Monomer and HBED-CC-04-DiF-Dimer have high binding affinity for fibroblast activation protein, IC50 values of 5.06+ -1.09 nM and 5.10+ -1.41 nM, respectively, and FAPI-04 (5.16+ -0.75 nM) are substantially consistent.
The invention is characterized in that 68 Ga-marked inhibitor radioactive probe for targeting fibroblast activation protein and has excellent performance 68 Ga labeling properties thanks to N, N' -bis [ 2-hydroxy-5- (carboxyethyl) -benzyl]Good Ga of ethylenediamine-N, N' -diacetic acid (HBED-CC) 3+ Bifunctional linker, HBED-CC and Ga 3+ High thermodynamic stability constant (log K) ML :38.5 Low energy required for coordination, therefore, [ 68 Ga]The Ga-HBED-CC labeling is rapid and efficient. Comparison [ 68 Ga]Ga-FAPI-04 needs to be heated at 100 ℃ for 20 minutes to prepare a product with the radiochemical purity of more than 90 percent 68 Ga-labeled inhibitor radioactive probe of targeted fibroblast activation protein can be rapidly prepared by heating at 95 ℃ for 5 minutes, and the radiochemical yield and radiochemical purity of the product are high (both>99%), high stability.
The invention is characterized in that 68 Ga-labeled fibroblast activation protein targeted inhibitor radioactive probe contains (S) -N- (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-ethoxy) -6- (3- (piperazin-1-yl) propoxy) quinoline-4-carboxamide group, which has good fibroblast activation protein affinity; in addition, the introduction of HBED-CC may increase tumor uptake. We expect [ [ 68 Ga]Ga-HBED-CC-04-DiF-Monomer and [ 68 Ga]Ga-HBED-CC-04-DiF-Dimer has good tumor affinity for achieving fibroblast activation protein, high tumor uptake value and long tumor residence time. Thus, the invention 68 Ga-labeled inhibitor radioactive probes for targeting fibroblast activation protein can be used as tumor positron molecular probes for tumor imaging.
The foregoing description is only illustrative of the preferred embodiments of the present invention and is not to be construed as limiting the scope of the invention, i.e., the invention is not to be limited to the details of the invention.

Claims (6)

1. 68 Ga-labeled inhibitor radioactive probes targeting fibroblast activation protein are respectively: [ 68 Ga]Ga-HBED-CC-04-DiF-Monomer or [ 68 Ga]Ga-HBED-CC-04-DiF-Dimer has the following structural formulas:
Figure FDA0003382433300000011
2. 68 the preparation method of the Ga-marked inhibitor radioactive probe for targeting fibroblast activation protein comprises the following steps: condensing the bifunctional linker HBED-CC and fibroblast activation protein inhibitor in the presence of alkali and condensing agent, removing protecting group with acid, dissolving the obtained product in dimethyl sulfoxide, adding 68 Ga]GaCl 3 Mixing the above solutions, and heating to obtain 68 Ga-labeled inhibitor-type radioactive probes targeting fibroblast activation proteins.
3. The method for preparing the fibroblast activation protein targeted inhibitor radioactive probe according to claim 2, wherein the method comprises the following steps: the alkali is N, N-diisopropylethylamine, and the addition amount is 3-5 equivalents; the condensing agent is 1-hydroxybenzotriazole and 1-ethyl- (3-dimethylaminopropyl) carbodiimide, and the addition amounts are 1 equivalent; the fibroblast activation protein inhibitor is (S) -N- (2- (2-cyano-4, 4-difluoro pyrrolidin-1-yl) -2-ethoxy) -6- (3- (piperazine-1-yl) propoxy) quinoline-4-carboxamide, and the addition amount is 1-5 equivalents; the acid was trifluoroacetic acid and the amount added was 3 ml.
4. The method for preparing the fibroblast activation protein targeted inhibitor radioactive probe according to claim 2, wherein the method comprises the following steps: the method comprises the following specific steps:
step 1: synthesis of labeled precursor of inhibitor-type radioactive probe targeting fibroblast activation protein
Dissolving (S) -N- (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-ethoxy) -6- (3- (piperazin-1-yl) propoxy) quinoline-4-carboxamide in anhydrous dimethylformamide, adding 1-hydroxybenzotriazole, N-diisopropylethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide and 3,3' - (((2,2,13,13-tetramethyl-4, 11-dioxo-3, 12-dioxa-6, 9-diazatetradecane-6, 9-diyl) bis (methylene)) bis (4-hydroxy-3, 1-phenyl)) dipropionic acid to the mixed solution, reacting at room temperature, adding ethyl acetate and saturated brine to the mixed solution for washing after overnight, and collecting an organic phase filtrate; the organic phase filtrate is dried with anhydrous sodium sulfate, filtered, and solid impurities are removed; removing the solvent in the filtrate by a rotary evaporator under reduced pressure, separating by a silica gel column by using a mixed solution of dichloromethane, methanol and 25% ammonia water (4:1:0.1, v/v/v), collecting components, removing the organic solvent in the components by using the rotary evaporator and an oil pump to obtain brown yellow oily matter, dissolving the obtained brown yellow oily matter in trifluoroacetic acid, stirring at room temperature, removing the solvent by using the rotary evaporator and the oil pump, and recrystallizing by using diethyl ether to obtain brown yellow solid; dissolving the obtained brown yellow solid in dimethyl sulfoxide, and purifying by Semi-HPLC to obtain brown yellow solid HBED-CC-04-DiF-Monomer;
step 2: labeling of inhibitor-based radioactive probes targeting fibroblast activation protein
Dissolving HBED-CC-04-DiF-Monomer obtained in step 1 in dimethyl sulfoxide, adding sodium acetate solution to obtain labeled precursor sodium acetate solution, eluting germanium gallium generator with high-purity hydrochloric acid solution to obtain [ 68 Ga]GaCl 3 Adding hydrochloric acid solution into sodium acetate solution as labeling precursor, mixing, reacting at 95deg.C, cooling to room temperature, and measuring its labeling rate by high performance liquid chromatography (radio-HPLC) with radioactive detector to obtain the product with radiochemical yield greater than 99% 68 Ga]Ga-HBED-CC-04-DiF-Monomer。
5. The method for preparing the fibroblast activation protein targeted inhibitor radioactive probe according to claim 2, wherein the method comprises the following steps: the method comprises the following specific steps:
step 1: synthesis of labeled precursor of inhibitor-type radioactive probe targeting fibroblast activation protein
Dissolving (S) -N- (2- (2-cyano-4, 4-difluoropyrrolidin-1-yl) -2-ethoxy) -6- (3- (piperazin-1-yl) propoxy) quinoline-4-carboxamide in anhydrous dimethylformamide, adding 1-hydroxybenzotriazole, N-diisopropylethylamine, 1-ethyl- (3-dimethylaminopropyl) carbodiimide and 3,3' - (((2,2,13,13-tetramethyl-4, 11-dioxo-3, 12-dioxa-6, 9-diazatetradecane-6, 9-diyl) bis (methylene)) bis (4-hydroxy-3, 1-phenyl)) dipropionic acid to the mixed solution, reacting at room temperature, adding ethyl acetate and saturated brine to the mixed solution for washing after overnight, and collecting an organic phase filtrate; the organic phase filtrate is dried with anhydrous sodium sulfate, filtered, and solid impurities are removed; removing the solvent in the filtrate by using a rotary evaporator under reduced pressure, separating by using a silica gel column by using a mixed solution (20:1:0.1, v/v/v) of dichloromethane, methanol and 25% ammonia water, wherein the volume ratio of the mixed solution is 20:1:0.1, collecting components, removing the organic solvent in the components by using the rotary evaporator and an oil pump to obtain a brown-red oily substance, dissolving the obtained brown-red oily substance in trifluoroacetic acid, stirring at room temperature, removing the solvent by using the rotary evaporator and the oil pump, and recrystallizing by using diethyl ether to obtain a brown-red solid; dissolving the obtained brown solid in dimethyl sulfoxide, and purifying by Semi-HPLC to obtain brown solid HBED-CC-04-DiF-Dimer;
step 2: labeling of inhibitor-based radioactive probes targeting fibroblast activation protein
Dissolving HBED-CC-04-DiF-Dimer obtained in step 2 in dimethyl sulfoxide, adding sodium acetate solution to obtain labeled precursor sodium acetate solution, eluting germanium gallium generator with high-purity hydrochloric acid solution to obtain 68 Ga]GaCl 3 Adding hydrochloric acid solution into sodium acetate solution as labeling precursor, mixing, reacting at 95deg.C, cooling to room temperature, and measuring its labeling rate by high performance liquid chromatography with radioactive detector to obtain the product with radiochemical yield greater than 99% 68 Ga]Ga-HBED-CC-04-DiF-Dimer。
6. The method for preparing the fibroblast activation protein targeted inhibitor radioactive probe according to claim 4 or 5, wherein the method comprises the following steps: in step 2, the test conditions of the high performance liquid chromatography with the radioactivity detector are as follows: the first mobile phase is 0.1% trifluoroacetic acid aqueous solution, the second mobile phase is 0.1% trifluoroacetic acid acetonitrile solution, and the gradient elution conditions are: 0-10 minutes, 100% -35% of a first mobile phase; 10-12 minutes, 35% -100% of the first mobile phase; 12-15 minutes, 100% of the first mobile phase; the flow rate of the mobile phase was 1 ml/min.
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