CN117731806A - Radionuclide-labeled denomab, precursor compound thereof, preparation method and application - Google Patents
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Abstract
The invention discloses radionuclide marked denomab, a precursor compound, a preparation method and application thereof, and belongs to the technical field of nuclear medicine. The precursor compound has a structure shown in a formula I-1, a formula I-2 or a formula I-3. The present invention also provides radionuclide-labeled compounds of the above precursor compounds. The preparation method of the precursor compound comprises the following steps: dinodizumabAnd reacting with p-SCN-Bn-DOTA, p-SCN-Bn-NOTA or p-SCN-Bn-DFO to obtain the compound shown in formula I-1, formula I-2 or formula I-3. The preparation method of the radionuclide marked denomab comprises the following steps: and (3) reacting the precursor compound with a radionuclide salt solution to obtain the radionuclide-marked denomab. The radionuclide marked denomab has simple marking method, proper reaction time and higher marking yield, and can realize the imaging and treatment effects on RANKL/RANK signal channel diseases such as metastatic bone tumor, bone giant cell tumor and multiple myeloma.
Description
Technical Field
The invention belongs to the technical field of nuclear medicine, and particularly relates to radionuclide marked denomab, a precursor compound thereof, a preparation method and application.
Background
Bone is a good site for distant metastasis of malignant tumors, with incidence inferior to lung and liver. Among all cancerous pains, bone destructive bone pains caused by bone metastasis such as lung cancer, breast cancer, prostate cancer, kidney cancer, thyroid cancer and the like are the most common symptoms. Malignant bone metastasis can lead to severe bone related events (skeletal related event, SRE) that manifest locally in lesions as bone pain, pathological fractures, vertebral compression fractures, bladder, rectal and reproductive dysfunction, systemic changes including hypercalcemia, renal failure, etc. Early diagnosis and treatment of solid bone metastasis can effectively improve prognosis and life quality of patients.
In physiological conditions, bone remodeling is continuously generated and absorbed depending on the biological activities of osteoblasts and osteoclasts, thereby achieving a stable equilibrium state. When tumor bone is transferred, the metastatic cancer cells need to activate the osteoclast to differentiate and mature, and then the osteoclast mediates bone absorption to cause the destruction of tumor bone so as to grow in a planting way. Proliferation and differentiation of osteoclasts are mainly regulated by RANK/RANKL signaling pathways, RANK nuclear factor κb receptor activators belong to the tumor necrosis factor (tumor necrosis factor, TNF) receptor family, expressed on many cell surfaces, such as osteoclast precursors, mature osteoclasts, dendritic cells, mammary epithelial cells, breast cancer cells, prostate cancer cells, etc. RANKL is a related ligand of RANK and can be produced by osteoblasts and their precursors, T cells, B cells and megakaryocytes. Binding of RANK to RANKL plays a critical role in osteoclast survival, differentiation and activation. Thus, RANKL, a RANK-targeting ligand, is a good choice for the treatment of bone metastases. The denomab can block RANKL to activate the receptor RANK on the surfaces of osteoclasts, osteoclast precursors and osteoclast-like giant cells, and inhibit the malignant circulatory process of cancer bone metastasis. Meanwhile, the denomab also has the anti-tumor effect. Because RANK exists not only in osteoclast but also in tumor cells, denomab is a monoclonal antibody targeting RANKL, can be combined with RANK receptor on tumor cells, inhibits occurrence and metastasis of tumor, and has direct tumor killing effect.
The current treatment methods for solid bone metastasis mainly comprise radiotherapy, chemotherapy, radionuclide therapy, pain relieving therapy, palliative surgery therapy, osteoclast inhibitor therapy and the like. Clinical osteoclast inhibitors mainly comprise bisphosphonates and denomab, the bisphosphonates have been widely used as anti-bone resorption agents for cancer bone metastasis, but the inhibition of cancer cell activity by bisphosphonates is limited, and clinically high-dose bisphosphonate treatment often causes jawbone necrosis. Denomab was first and only approved in china as a RANKL inhibitor, and denomab was first approved in the european union in 2010, called a precise bone targeting drug, for the treatment of postmenopausal osteoporosis, solid bone metastases, and advanced or inoperable bone giant cell tumors. In addition, researches prove that the denomab has the effects of prolonging the first SRE occurrence time of patients, reducing the risk of repeated SRE, delaying pain and the like when being applied to solid tumors such as breast cancer, prostatic cancer, lung cancer and the like and multiple myeloma. The clinically usual dose is 120 mg/time/4 weeks. Compared with bisphosphonates, the denomab has targeting property and direct anti-tumor effect; the clinical curative effect of the medicine is superior to that of bisphosphonate medicines, and the medicine is still effective for patients who fail to be treated by the bisphosphonate medicines; in addition, the denomab has good safety, and patients have fewer side effects of nephrotoxicity.
68 Ga、 64 Cu、 89 Zr、 90 Y、 111 In、 133 Lu、 225 Ac is a medical isotope with excellent nuclear properties. The location and distribution in the corresponding biomacromolecule bound thereto can be conveniently determined using DOTA (1,4,3,10-tetraazacyclododecane-1,4,3,10-tetracarboxylic acid), NOTA (1, 4, 3-triazacyclononane-N, N', N "-triacetic acid) or DFO (desferrioxamine) as a chelator, and a radionuclide-labeled monoclonal antibody as a probe. The radionuclide is used for marking the denomab with smaller clinical dosage, the radionuclide is indirectly introduced into the human body, so that the radionuclide acts on the RANKL/RANK signal path, the proliferation and differentiation development of osteoclasts are inhibited, the bone resorption is reduced, and the bone pain is relieved, especially the radionuclide is used for diagnosing and treating solid bone metastasis and bone giant cell tumor, and the radionuclide has obvious advantages, has small toxic and side effects and is a safe and effective treatment mode.
Therefore, aiming at the RANKL/RANK signal channel, the development of a molecular probe with high specificity for diagnosis and treatment of the channel has great significance. There is a great clinical need to develop new diagnostic and therapeutic approaches to early diagnosis of solid bone metastases, relief of bone pain, improvement of patient quality of life and provision of new therapeutic approaches for bone metastases, bone giant cell tumors.
Disclosure of Invention
It is an object of the present invention to provide a precursor compound of denomab which can be labeled with a radionuclide and which can be used as a drug for targeting a tumor or a molecular imaging agent after being labeled with a radionuclide.
The second object of the present invention is to provide radionuclide-labeled denomab, which has the advantages of simple labeling method, proper reaction time and high labeling yield, and can realize the imaging and treatment effects on RANKL/RANK signal channel diseases such as metastatic bone tumor, bone giant cell tumor and multiple myeloma.
It is a further object of the present invention to provide a method for preparing a radionuclide-labeled denomab precursor compound.
The fourth object of the present invention is to provide a method for preparing radionuclide-labeled denomab.
It is a fifth object of the present invention to provide a radionuclide-labeled denomab precursor compound, and the use of radionuclide-labeled denomab.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the radionuclide marked denomab precursor compound or pharmaceutically acceptable salt thereof provided by the invention has the structure shown in the formula I-1, the formula I-2 or the formula I-3:
wherein the method comprises the steps ofIs denomab.
The radionuclide marked denomab or pharmaceutically acceptable salt thereof provided by the invention has the structure shown in the formula II-1, the formula II-2 or the formula II-3:
wherein the method comprises the steps ofIs denomab, A is a radionuclide.
In some embodiments of the invention, A is 68 Ga、 64 Cu、 89 Zr、 90 Y、 111 In、 1133 Lu、 225 Ac。
In some embodiments of the invention, in formula II-1, formula II-2, A is independently selected from 68 Ga、 64 Cu、 90 Y、 111 In、 133 Lu、 225 Ac;
in the formula II-3, A is 89 Zr。
In some embodiments of the invention, the radiochemical purity is greater than or equal to 95%.
In some embodiments of the invention, when the chelating agent is selected from DOTA/NOTA, e.g. 68 Ga、 133 Lu is marked to realize diagnosis and treatment integration, namely, under the condition of the same chelating agent, the appropriate nuclide marked DOTA/NOTA-denomab is used for diagnosing RANKL/RANK signal channel diseases such as metastatic bone tumor, bone giant cell tumor and multiple myeloma, and then nuclide treatment (namely, the nuclide marked DOTA/NOTA-denomab) is further carried out, and nuclide is selected 89 Zr, the chelating agent can only select DFO, which can be used as a more choice for diagnosing RANKL/RANK signaling pathway diseases.
The preparation method of the radionuclide marked denomab precursor compound provided by the invention comprises the following steps: reacting denomab with p-SCN-Bn-DOTA to prepare a compound of formula I-1; preferably, the reaction temperature is 33+ -2deg.C, more preferably 33 deg.C;
when the precursor compound is shown as the formula I-2, the preparation method comprises the following steps: reacting denomab with p-SCN-Bn-NOTA to prepare a compound of formula I-2; preferably, the reaction temperature is 33+ -2deg.C, more preferably 33 deg.C;
when the precursor compound is shown as the formula I-3, the preparation method comprises the following steps: reacting the denomab with p-SCN-Bn-DFO to prepare a compound of a formula I-3; preferably, the reaction temperature is 33.+ -. 2 ℃, more preferably 33 ℃ constant temperature reaction.
In some embodiments of the invention, the molar ratio of denomab to p-SCN-Bn-DOTA is 1:5-15, preferably 1:10;
molar ratio of denomab to p-SCN-Bn-NOTA 1:5-15, preferably 1:10;
molar ratio of denomab to p-SCN-Bn-DFO 1:3-8, preferably 1:5.
the preparation method of the radionuclide marked denomab is characterized in that the precursor compound is reacted with radionuclide salt solution to obtain the radionuclide marked denomab.
In some embodiments of the present invention, when the precursor compound is of formula I-1 or formula I-2, the method for preparing radionuclide-labeled denomab comprises the steps of:
uniformly mixing a sodium acetate solution and a radionuclide salt solution, regulating the pH value of the mixed solution, adding a compound of formula I-1 or a compound of formula I-2 into the mixed solution, and reacting to generate radionuclide-labeled denomab; preferably, the radionuclide is 68 Ga、 64 Cu、 90 Y、 111 In、 133 Lu or 225 Ac；
When the precursor compound is of formula I-3, the radionuclide is 89 The preparation method of the Zr, radionuclide-labeled denomab comprises the following steps: taking out 89 Zr-oxalate solution, adjusting pH to be neutral; to the direction of 89 And adding the compound shown in the formula I-3 into the Zr-oxalate solution to generate the radionuclide marked denomab.
The radionuclide marked denomab precursor compound or pharmaceutically acceptable salt thereof provided by the invention or the radionuclide marked denomab or pharmaceutically acceptable salt thereof as claimed in any one of claims 2-4 is applied to the preparation of molecular imaging agents or/and tumor targeting drugs, preferably the preparation of molecular imaging agents or tumor targeting drugs; preferably, the tumour is a RANKL/RANK signalling pathway disease.
The names corresponding to the Chinese and English abbreviations are as follows:
DOTA:1,4,3,10-tetraazacyclododecane-1,4,3,10-tetracarboxylic acid
NOTA:1,4, 3-Triazacyclononane-N, N' -triacetic acid
DFO: deferoxamine
p-SCN-Bn-DOTA:2- [ (4-Isothiocyanophenyl) methyl ] -1,4,3,10-tetraazacyclododecane-1,4,3,10-tetraacetic acid
p-SCN-Bn-NOTA:2- (4-isothiocyanatophenyl) -1,4, 3-triazacyclononane-1, 4, 3-triacetic acid
p-SCN-Bn-DFO: deferoxamine-benzoyl-N-chlorosuccinimide
DMSO: dimethyl sulfoxide
Compared with the prior art, the invention has the following beneficial effects:
the invention has scientific design and ingenious conception, creatively combines the chelating agent and the denomab to form a new compound, and obtains the radionuclide marked denomab through radionuclide marking.
In the prior art, the dosage of the clinical denomab for treating solid bone metastasis is 1 time every 4 weeks and 120mg every time; in the present invention, however, the active agent is a radionuclide 68 Ga、 64 Cu、 89 Zr、 90 Y、 111 In、 133 Lu、 225 The Ac label is low in precursor mass dose (microgram scale), and is used as a single dose of about 10mg for tumor targeted therapeutic.
In addition, the radionuclide marked denomab has simple marking method, proper reaction time and higher marking yield, the radioactive medicament can realize the imaging of solid bone metastasis and bone giant cell tumor,but also can treat and relieve the bone pain aiming at the corresponding focus, and can better exert 68 Ga、 64 Cu、 89 Zr、 90 Y、 111 In、 133 Lu、 225 Imaging or therapeutic effects of Ac and DOTA-denomab, NOTA-denomab or DFO-denomab against RANKL/RANK signaling pathway diseases such as metastatic bone tumor, bone giant cell tumor, and multiple myeloma.
Drawings
FIG. 1 is a mass spectrum of DOTA-denomab;
FIG. 2 is a mass spectrum of NOTA-dienomolast;
FIG. 3 is a drawing 68 GaCl 3 Amplifying a pure measurement result graph;
FIG. 4 is a diagram 68 Ga-DOTA-denomab radiometric pure measurement result diagram;
FIG. 5 is a diagram 133 LuCl 3 Amplifying a pure measurement result graph;
FIG. 6 is a diagram 133 A Lu-DOTA-denomab radiometric pure measurement result graph;
FIG. 7 is a diagram 68 Micro PET/CT imaging of Ga-DOTA-dienomolast in normal mice; wherein, the left image is a micro PET/CT image of 30 minutes after injection; the right panel is a micro PET/CT image at 60 minutes post injection.
FIG. 8 is a diagram of 133 Micro PET/CT imaging of Lu-DOTA-denomab in normal mice; wherein, the left image is a micro SPECT/CT image of 3 days after injection; the right panel is a micro SPECT/CT image 14 days after injection.
FIG. 9 shows normal mouse tail intravenous injection 133 Different time points after Lu-DOTA-denomab are primarily organ biodistribution of interest; wherein a, b, c, d, e, f, g, h represents 2h, 4h, 24h, 32h, 120h, 168h, 240h, 336h in sequence.
FIG. 10 shows intravenous injection of 33MBq into the tail of a normal mouse 133 Pathological figures of tissue and organs 28 days after Lu-DOTA-denomab; the names corresponding to the reference numerals in fig. 10 are: a is a heart; b, liver; c, spleen; lung; e, stomach; f, kidney; g, brain; h, small intestine; muscle; j, bone marrow.
FIG. 11 shows intravenous injection of 3.4MBq into the tail of mice bearing breast cancer MCF-3 bone metastases 133 The Lu-DOTA-denomab is a 6-hour image of the tumor-bearing portion of the tibia, and the arrow in the image shows the image of the tumor-bearing portion of the mouse bearing the breast cancer MCF-3 bone metastasis.
Detailed Description
In order to make the technical problems, technical solutions and advantages to be solved more apparent, the following detailed description will be given with reference to the accompanying drawings and specific embodiments.
The following examples are illustrative of the invention and are not intended to limit the scope of the invention. Modifications and substitutions to methods, procedures, or conditions of the present invention without departing from the spirit and nature of the invention are intended to be within the scope of the present invention.
The technical means used in the examples are conventional means well known to those skilled in the art unless otherwise indicated; the reagents used in the examples were all commercially available unless otherwise specified.
The denomab solution used in the examples of the present invention was derived from Shanghai microphone Lin Biochemical technology Co., ltd, and had a concentration of 62.2mg/mL.
Example 1
The embodiment discloses a preparation method of a compound (DOTA-denomab) of a formula I-1, which specifically comprises the following steps:
s1: 0.16ml of Deinomab solution containing about 10mg of Deinomab was removed by centrifugation with a small ultrafiltration tube (10K) at 13000rpm/min,4℃for 10min. Adding 0.15Mol/L NaHCO to the concentrated denomab 3 (pH value-9.0) centrifuging again, repeating for 3 times, and ensuring the concentration to be more than 10mg/mL after the solvent exchange of the sample;
s2: adding the antibody solution into a centrifuge tube with the volume of 1.5mL, and adding p-SCN-Bn-DOTA with the concentration of 20mg/mL into the centrifuge tube (taking DMSO solution as a solvent), wherein the molar ratio of the denomab to the p-SCN-Bn-DOTA is 1:10 The mixture is reacted for 1h (30 rpm/min) by a shaking table at the constant temperature of 33 ℃;
s3: the reaction was stopped by adding the sample after the reaction to an ultrafiltration tube, adding 0.5Mol/L sodium acetate, replenishing to about 400. Mu.L, centrifuging to remove the solution by ultrafiltration (13000 rpm/min,4 ℃,10 min), adding 0.5Mol/L sodium acetate again (pH 5-5.5), centrifuging repeatedly three times, and collecting the product to obtain the precursor compound.
S4: the BCA protein concentration assay kit was used to determine the precursor compounds (i.e., modified antibody concentrations) and sent to mass spectrometry. The mass spectrum of the compound of formula I-1 (DOTA-denomab) is shown in figure 1.
Example 2
The embodiment discloses a preparation method of a compound (NOTA-denomab) of formula I-2, which specifically comprises the following steps:
s1: 0.16ml of Deinomab solution containing about 10mg of Deinomab was removed by centrifugation with a small ultrafiltration tube (10K) at 13000rpm/min,4℃for 10min. Adding 0.15Mol/L NaHCO to the concentrated denomab 3 (pH value-9.0) centrifuging again, repeating for 3 times, and ensuring the concentration to be more than 10mg/mL after the solvent exchange of the sample;
s2: adding the antibody solution into a centrifuge tube with the volume of 1.5mL, and adding p-SCN-Bn-NOTA (taking DMSO solution as a solvent) with the concentration of 20mg/mL into the centrifuge tube, wherein the molar ratio of the denomab to the p-SCN-Bn-NOTA is 1:10 The mixture is reacted for 1h (30 rpm/min) by a shaking table at the constant temperature of 33 ℃;
s3: the reaction was stopped by adding the sample after the reaction to an ultrafiltration tube, adding 0.5Mol/L sodium acetate, replenishing to about 400. Mu.L, centrifuging to remove the solution by ultrafiltration (13000 rpm/min,4 ℃,10 min), adding 0.5Mol/L sodium acetate again (pH 5-5.5), centrifuging repeatedly three times, and collecting the product to obtain the precursor compound.
S4: the BCA protein concentration assay kit was used to determine the precursor compounds (i.e., modified antibody concentrations) and sent to mass spectrometry. The mass spectrum results of the compound of formula I-1 (NOTA-dienomolast) are shown in FIG. 2.
Example 3
The embodiment discloses a preparation method of an I-3 compound (DFO-denomab) of the invention, which comprises the following steps:
s1: taking 0.16ml of Deinomab solution containing about 10mg of Deinomab, centrifuging to remove solution concentrated MAB by using a small ultrafiltration tube (10K), wherein the centrifuging condition is 13000rpm/min,4 ℃ and 10min. Adding 0.15Mol/L NaHCO to the concentrated denomab 3 (pH value-9.0) centrifuging again, repeating for 3 times, and ensuring the concentration to be more than 10mg/mL after the solvent exchange of the sample;
s2: adding the antibody solution into a centrifuge tube with the volume of 1.5mL, adding p-SCN-Bn-DFO with the concentration of 20mg/mL into the centrifuge tube (taking DMSO solution as a solvent), wherein the molar ratio of the denomab to the p-SCN-Bn-DFO is 1:10 The mixture is reacted for 1h (30 rpm/min) by a shaking table at the constant temperature of 33 ℃;
s3: the reaction was stopped by adding the sample after the reaction to an ultrafiltration tube, adding 0.15Mol/L sodium acetate, replenishing to about 400. Mu.L, removing the solution by ultrafiltration and centrifugation (13000 rpm/min,4 ℃,10 min), adding 0.15Mol/L sodium acetate again (pH-3), and repeating centrifugation three times, and collecting the product to obtain the precursor compound.
S4: the BCA protein concentration assay kit was used to determine the precursor compounds (i.e., modified antibody concentrations) and sent to mass spectrometry.
Example 4
The embodiment discloses 68 The method of Ga-labeled DOTA-denomab, DOTA-denomab of this example was prepared as in example 1.
S1, taking the mixture with the concentration of 5mCi/mL 68 GaCl 3 Mixing with 0.25Mol/L sodium acetate solution at a volume ratio of 4:1, measuring pH value, and regulating pH value to 3.0-3.4 with PBS (pH 3.4);
s2, taking a solution with the pH value adjusted, adding 100 mug of a compound (DOTA-denomab) of the formula I-1 into the solution, uniformly mixing, and then incubating at 33 ℃ for reaction for 10 minutes to generate 68 Ga-DOTA-dienomotuzumab.
S3, purifying the solution after incubation reaction by using a PD-10 column: the PD-10 column is firstly balanced by sterile physiological saline, 5ml of the PD-10 column is added each time, gravity flow velocity is used for drying, and the process is repeated for 5 times; then loading, adding the reaction solution of S2 into PD10 column, eluting with sterile physiological saline (natural flow rate), and collecting to obtain purified product 68 Ga-DOTA-dienomotuzumab. Followed by Thin Layer Chromatography (TLC) 68 Radiochemical purity of Ga-DOTA-denomab.
Example 5
The embodiment discloses 68 The method of Ga-labeled NOTA-Denocomoab of this example was prepared as in example 2. The method for preparing the compound of the formula I-2 comprises the following steps:
s1, taking the mixture with the concentration of 5mCi/mL 68 GaCl 3 Mixing with 0.25Mol/L sodium acetate solution, measuring pH, and adjusting pH to 3.0-3.4 with PBS (pH 3.4);
s2, taking a solution with the pH value adjusted, adding 100 mug of a compound (NOTA-denomab) of the formula I-2 into the solution, uniformly mixing, and then incubating at 33 ℃ for reaction for 10 minutes to generate 68 Ga-NOTA-dienomotuzumab.
S3, purifying the solution after incubation reaction by using a PD-10 column: the PD-10 column is firstly balanced by sterile physiological saline, 5ml of the PD-10 column is added each time, gravity flow velocity is used for drying, and the process is repeated for 5 times; loading, adding the reaction solution of S2 into PD10 column, eluting with sterile physiological saline (natural flow rate), and collecting to obtain purified product 68 Ga-NOTA-dienomotuzumab. Followed by Thin Layer Chromatography (TLC) 68 Radiochemical purity of Ga-NOTA-denomab.
Example 6
The embodiment discloses 89 The method for marking DFO-denomab by Zr specifically comprises the following steps:
s1, taking about 3.3 mu L 89 Zr-oxalate solution (3.5 MBq), adding 0.9 mu L of sodium carbonate solution with the concentration of 0.5Mol/L, uniformly mixing, and adjusting the pH value to 3;
s2, taking about 150 mug of DFO-denomab to the solution of which the pH value is regulated by S1, standing for about 20min at room temperature, and fully reacting to generate the radioactive marker 89 Zr-DFO-denomab.
S3, purifying the solution after incubation reaction by using a PD-10 column: the PD-10 column is firstly balanced by sterile physiological saline, 5ml of the PD-10 column is added each time, gravity flow velocity is used for drying, and the process is repeated for 5 times; loading, adding the reaction solution of S2 into PD10 column, eluting with sterile physiological saline (natural flow rate), and collecting to obtain purified product 89 Zr-DFO-denomab. Followed by Thin Layer Chromatography (TLC) 89 Radiochemical purity of Zr-DFO-denomab.
Example 3
The embodiment discloses 133 The method of labeling DOTA-denomab by Lu, DOTA-denomab of this example was prepared as in example 1.
S1, taking the concentration of 10mCi/mL 133 LuCl 3 Mixing with 0.05Mol/L sodium acetate solution at a volume ratio of 1:1, measuring pH value, and regulating pH value to 3.0-3.4 with PBS (pH 3.4);
s2, taking a solution with the pH value adjusted, adding 150 mug of a compound (DOTA-denomab) of the formula I-1 into the solution, uniformly mixing, and then incubating at 33 ℃ for reaction for 60 minutes to generate 133 Lu-DOTA-denomab.
S3, purifying the solution after incubation reaction by using a PD-10 column: the PD-10 column is firstly balanced by sterile physiological saline, 5ml of the PD-10 column is added each time, gravity flow velocity is used for drying, and the process is repeated for 5 times; loading, adding the reaction solution of S2 into PD10 column, eluting with sterile physiological saline (natural flow rate), and collecting to obtain purified product 133 Lu-DOTA-denomab. Followed by Thin Layer Chromatography (TLC) 133 Radiochemical purity of Lu-DOTA-denomab.
Test example 1
The test example discloses the radiochemical purity determination of the radionuclide marked denomab, which is specifically as follows:
spotting was performed using thin layer chromatography paper using citric acid buffer (0.5 m, ph=5) as developing agent, and the radiochemical purity of the radiolabel was determined using a gamma counter.
Wherein, 68 GaCl 3 the amplification purity measurement result of (c) is shown in figure 3, 68 the Ga-DOTA-denomab radiometric purity determination result is shown in figure 4; indicating the present invention 68 The radiochemical purity of Ga-DOTA-denomab is 99.39%.
Wherein, 133 LuCl 3 the amplification purity measurement results of (c) are shown in FIG. 5, 133 the result of the pure determination of the Lu-DOTA-denomab radiochemistry is shown in figure 6; indicating the present invention 133 The radiochemical purity of Lu-DOTA-denomab is 95.09%.
Test example 2
The test example discloses an imaging research test of nuclide-labeled DOTA-denomab in normal mice.
(1) 68 Development study of Ga-DOTA-dienomomab in Normal mice
Taking normal mice, and performing tail intravenous injection 68 After 3.3MBq of Ga-DOTA-dienomolast, micro PET/CT imaging is carried out respectively at 30min, 60min, 90min and 120min after injection, and in-vivo distribution and metabolism characteristics are observed. 68 The micro PET/CT image (30 min, 60 min) of Ga-DOTA-dienomomab in normal mice is shown in figure 3, and the result shows that 68 Ga-DOTA-dienomolast is cleared faster in normal tissues.
(2) 133 Development study of Lu-DOTA-Denocomoab in Normal mice
Taking normal mice, and performing tail intravenous injection 133 The Lu-DOTA-denomab 3.4MBq was subjected to micro SPECT/CT imaging at 1d, 3d, 5d, 3d, 14d and 21d after injection, respectively, and in vivo distribution and metabolic characteristics were observed. 133 The micro SPECT/CT images (3 d, 14 d) of Lu-DOTA-denomab in normal mice are shown in FIG. 8, and the results show 133 Lu-DOTA-dienomomab is taken up in liver and spleen and cleared more rapidly in the rest of normal tissues.
Test example 3
The experimental example discloses the in vivo biodistribution experimental study of the nuclide-marked DOTA-denomab in normal mice.
Using physiological saline to label 133 Lu-DOTA-Deinomab was diluted and 150. Mu.L was sterilized with alcohol and then the skin of the tail vein of the mice was sterilized with 1ml insulin needle 133 Lu-DOTA-denomab (3.4 MBq) was tail intravenously injected into mice, and mice were sacrificed under 2h, 4h, 24h, 32h, 120h, 168h, 240h, 336h anesthesia, heart, liver, spleen, lung, kidney, stomach, intestine, muscle, bone, brain, and blood were collected, radioactivity was measured using a gamma radioimmunometer after weighing, and% ID/g values of biodistribution were expressed as a percentage of injected dose per gram using mean ± standard differential analysis results. The results are shown in FIG. 9. The results show that the method has the advantages of, 133 after Lu-DOTA-denomab injection into the body, it follows the antibody drive distribution to the whole bodyThe concentration of the whole blood is highest, and the whole blood is liver and spleen, and hardly stays in normal tissues, so that the safety risk is greatly reduced. Although it is mainly metabolized by the liver and spleen, it is excreted by the kidney, which has potential advantages for chronic kidney disease patients.
Test example 4
The test example discloses toxicity experimental study test of nuclide-labeled DOTA-denomab in normal mice.
16 normal Kunming mice were randomly divided into 4 groups and injected with 3.3MBq, 18.5MBq, 33MBq, respectively 133 Lu-DOTA-denomab and normal saline group, and the health status, body weight and diet change of the mice were recorded. Mice were sacrificed 28 days later and visually observed 133 The Lu-DOTA-denomab is changed (form, size and texture) compared with the control group, and important tissue organs are taken for paraffin embedding, slicing, HE staining and microscopic observation.
Markers 133 Lu-DOTA-denomab is injected into normal mice for 28 days, no death occurs, and during observation period, the feed consumption and activity of the mice in each group (high dose group: 33MBq; medium dose group: 18.5MBq; low dose group: 3.3MBq; control group: normal saline) are not obviously reduced, and no vomiting, diarrhea and other conditions occur. During the observation period, the body weight of the 4 groups of mice increased with the increase of time. After the observation period is finished, the mice in each group are dissected, and the abnormal changes of the sizes, colors, forms and textures of tissues and organs of the mice in each group are not found. After paraffin embedding, slicing and HE staining are carried out on tissue organs of each group of mice, the observation results show that compared with the control group, the cell sizes, the morphology and the proportion of each tissue mirror of the mice in the high, medium and low dose groups are not obviously different, and no obvious abnormal pathological changes such as denaturation, necrosis and the like occur. As shown in fig. 10.
Test example 5
This test example discloses 133 Imaging study trial of Lu-DOTA-dienomolast in tumor-bearing mice.
Several breast cancer MCF-3 bone metastasis model mice are taken and injected 133 After Lu-DOTA-denomab, micro SPECT/CT was performedFor example, important viscera, bone and muscle of the side, bone of the side and muscle distribution and metabolism of the side are observed. As shown in fig. 11, a right tibia tumor-bearing portion image of a mouse bearing breast cancer MCF-3 bone metastasis, which shows the targeting of the nuclide marker to a tumor model.
Finally, it should be noted that: the above embodiments are merely preferred embodiments of the present invention to illustrate the technical solution of the present invention, but not to limit the scope of the present invention. All the changes or color-rendering which are made in the main design idea and spirit of the invention and which are not significant are considered to be the same as the invention, and all the technical problems which are solved are included in the protection scope of the invention; in addition, the technical scheme of the invention is directly or indirectly applied to other related technical fields, and the technical scheme is included in the scope of the invention.
Claims (10)
1. A radionuclide-labeled denomab precursor compound or a pharmaceutically acceptable salt thereof, characterized in that the radionuclide-labeled denomab precursor compound has a structure as shown in formula I-1, formula I-2 or formula I-3:
wherein the method comprises the steps ofIs denomab.
2. Radionuclide-labeled denomab or pharmaceutically acceptable salt thereof, characterized in that the structure is shown in formula II-1, formula II-2 or formula II-3:
wherein the method comprises the steps ofIs the groundNormab, A is a radionuclide.
3. The radionuclide-labeled denomab or pharmaceutically acceptable salt thereof according to claim 2, characterized in that a is 68 Ga、 64 Cu、 89 Zr、 90 Y、 111 In、 177 Lu、 225 Ac。
4. The radionuclide-labeled denomab or pharmaceutically acceptable salt thereof of claim 2, characterized in that in formula II-1, formula II-2, a is independently selected from 68 Ga、 64 Cu、 90 Y、 111 In、 177 Lu、 225 Ac; in the formula II-3, A is 89 Zr。
5. The radionuclide-labeled denomab or pharmaceutically acceptable salt thereof according to any of claims 2-4, having a radiochemical purity of 95% or more.
6. The method of preparing a radionuclide-labeled denomab precursor compound of claim 1, wherein when the precursor compound is of formula I-1, the method comprises the steps of: reacting denomab with p-SCN-Bn-DOTA to prepare a compound of formula I-1; preferably, the reaction temperature is 37+ -2deg.C, more preferably 37 deg.C;
when the precursor compound is shown as the formula I-2, the preparation method comprises the following steps: reacting denomab with p-SCN-Bn-NOTA to prepare a compound of formula I-2; preferably, the reaction temperature is 37+ -2deg.C, more preferably 37 deg.C;
when the precursor compound is shown as the formula I-3, the preparation method comprises the following steps: reacting the denomab with p-SCN-Bn-DFO to prepare a compound of a formula I-3; preferably, the reaction temperature is 37.+ -. 2 ℃, more preferably 37 ℃ constant temperature reaction.
7. The method of preparing a radionuclide-labeled denomab precursor compound according to claim 6, characterized in that the molar ratio of denomab to p-SCN-Bn-DOTA is 1:5-15, preferably 1:10;
molar ratio of denomab to p-SCN-Bn-NOTA 1:5-15, preferably 1: :10;
molar ratio of denomab to p-SCN-Bn-DFO 1:3-8, preferably 1:5.
8. the method for preparing radionuclide-labeled denomab according to any one of claims 2-4, wherein the precursor compound is reacted with a radionuclide salt solution to obtain radionuclide-labeled denomab.
9. The method of preparing radionuclide-labeled denomab according to claim 8, wherein when the precursor compound is of formula I-1 or formula I-2, the method of preparing radionuclide-labeled denomab comprises the steps of:
uniformly mixing a sodium acetate solution and a radionuclide salt solution, regulating the pH value of the mixed solution, adding a compound of formula I-1 or a compound of formula I-2 into the mixed solution, and reacting to generate radionuclide-labeled denomab; preferably, the radionuclide is 68 Ga、 64 Cu、 90 Y、 111 In、 177 Lu or 225 Ac；
When the precursor compound is of formula I-3, the radionuclide is 89 The preparation method of the Zr, radionuclide-labeled denomab comprises the following steps: taking out 89 Zr-oxalate solution, adjusting pH to be neutral; to the direction of 89 And adding the compound shown in the formula I-3 into the Zr-oxalate solution to generate the radionuclide marked denomab.
10. The use of a radionuclide-labeled denomab precursor compound or a pharmaceutically acceptable salt thereof according to claim 1, or a radionuclide-labeled denomab or a pharmaceutically acceptable salt thereof according to any one of claims 2-4, in the preparation of a molecular imaging agent and/or a tumor targeting drug, preferably in the preparation of a drug that is both a molecular imaging agent and a tumor targeting drug; preferably, the tumour is a RANKL/RANK signalling pathway disease.
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