Radiopharmaceutical composition, preparation method therefor, and use thereof

Abstract

Disclosed are a radiopharmaceutical composition, a preparation method therefor, and use thereof. Specifically, the present invention relates to a composition comprising a carbonic anhydrase IX protein-targeted radiopharmaceutical and a preparation method therefor. The pharmaceutical composition does not comprise a stabilizer and can be stored at a room temperature of 30 °C for at least 6 hours, far exceeding the half-life of 18F of 109.8 minutes, thereby demonstrating good stability and promising clinical application prospects. In addition, the preparation method is simple, can be conducted under mild conditions, and is beneficial to industrial production.

Description

Radiopharmaceutical compositions, their preparation methods and uses

[0001] This application claims priority to Chinese patent application filed on February 5, 2025, with application number 202510130632.8, entitled "Radiopharmaceutical Composition and Preparation Method Thereof and Use Thereof". Technical Field

[0002] This invention relates to the pharmaceutical field, specifically to a radiopharmaceutical targeting the carbonic anhydrase IX (CAIX) protein. Background Technology

[0003] Renal cell carcinoma (RCC) is the most common kidney vegetation. Among RCC cases, the clear cell subtype (ccRCC) is the most prevalent, accounting for up to 70% of all RCC cases. A common feature of ccRCC is the loss of the Von Hippel-Lindau (VHL) tumor suppressor gene. This loss of VHL subsequently leads to overexpression of carbonic anhydrase IX (CAIX). CAIX is a membrane-associated enzyme responsible for catalyzing the reversible hydrolysis of carbon dioxide to bicarbonate anions and protons. Overexpression of CAIX has been confirmed in approximately 95% of ccRCC tumor samples, making it a useful biomarker for this disease.

[0004] Specific radiolabeling using chemical methods and radionuclides. Radionuclides are aggregated at the tumor site through targeted structures, emitting particles or rays to achieve therapeutic or diagnostic effects. However, due to the continuous decay of radionuclides releasing high-energy particles or rays, the covalent bonds in the molecules of radiopharmaceutical formulations break during production and storage—a phenomenon known as radiation degradation. This degradation may lead to a decrease in the specificity of radionuclide complexes, resulting in reduced efficacy and / or an increase in undesirable side effects. The stability and high purity of radiopharmaceuticals have become issues of concern for those skilled in the art.

[0005] To improve the purity and stability of radiopharmaceuticals, various strategies have been explored, such as adding stabilizers. However, adding stabilizers may negatively impact the complexation of the radionuclide with the chelating agent, or may result in limited solubility and precipitation from solution. Therefore, developing radiopharmaceutical formulations with good stability, few side effects, and high safety has significant scientific research value and broad application prospects. Summary of the Invention

[0006] This invention provides a stable radiopharmaceutical composition targeting carbonic anhydrase IX (CAIX) protein, which can be stored at room temperature (30°C) for at least 6 hours, far exceeding... 18With a half-life of 109.8 minutes, F can be used to diagnose and / or treat diseases that overexpress carbonic anhydrase IX protein, and has great potential for clinical application.

[0007] The present invention also provides a method for preparing the pharmaceutical composition of the present invention, which has a high yield, is simple to operate, and is under mild conditions, which is conducive to industrial production.

[0008] In one aspect, the present invention provides a pharmaceutical composition comprising a complex and water;

[0009] The complex is a complex formed by the complexation of a radionuclide and a precursor compound; the precursor compound is a carbonic anhydrase IX targeting ligand linked to the chelating agent.

[0010] In another aspect, the present invention provides a method for preparing the pharmaceutical composition of the present invention, comprising: a) reacting a radionuclide with a precursor compound to form a complex; preferably, mixing a solution containing the precursor compound with a solution containing the radionuclide to carry out the reaction;

[0011] Wherein, the precursor compound is as defined in this invention, and the radionuclide is as defined in this invention.

[0012] In another aspect, the present invention provides pharmaceutical formulations comprising the pharmaceutical compositions of the present invention; optionally, the pharmaceutical formulations further comprise pharmaceutically acceptable carriers or excipients.

[0013] In another aspect, the present invention provides a pharmaceutical preparation obtained by the preparation method of the present invention.

[0014] In another aspect, the present invention provides the use of the pharmaceutical compositions or pharmaceutical preparations of the present invention in the preparation of reagents and / or medicaments for the diagnosis and / or treatment of one or more tumors or cells expressing carbonic anhydrase IX.

[0015] In another aspect, the present invention provides pharmaceutical compositions or pharmaceutical preparations of the present invention for the diagnosis and / or treatment of one or more tumors or cells expressing carbonic anhydrase IX.

[0016] In another aspect, the present invention provides a method for diagnosing and / or treating one or more tumors or cells expressing carbonic anhydrase IX, wherein the method comprises administering a pharmaceutical composition or pharmaceutical preparation of the present invention to a subject.

[0017] In another aspect, the tumor expressing carbonic anhydrase IX is selected from one or more of the following: kidney cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, melanoma, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head and neck cancer, astrocytoma, and oral cancer.

[0018] In another aspect, the diagnostic method is selected from optical imaging and / or radionuclide imaging; preferably, the radionuclide imaging is selected from PET imaging and / or SPECT imaging.

[0019] In another aspect, the treatment is selected from radiotherapy and / or fluorescent surgical navigation performed as an adjunct to surgery.

[0020] In another aspect, the present invention provides a method for imaging tissue expressing carbonic anhydrase IX, comprising administering the pharmaceutical composition or pharmaceutical preparation of the present invention to the tissue, and imaging the tissue after administration.

[0021] In another aspect, the imaging is emission computed tomography, performed by positron emission tomography or single-photon emission computed tomography. Detailed Implementation Plan

[0022] In one embodiment, the present invention provides a pharmaceutical composition comprising a complex and water;

[0023] The complex is a complex formed by the complexation of a radionuclide and a precursor compound; the precursor compound is a carbonic anhydrase IX targeting ligand linked to the chelating agent.

[0024] In a more specific embodiment, the present invention provides the above-described pharmaceutical composition, wherein the portion of the carbonic anhydrase IX targeting ligand in the prodrug compound is selected from the following structures: Where n = 0 or 2; preferred

[0025] In a more specific embodiment, the present invention provides the above-described pharmaceutical composition, wherein the chelating agent portion of the prodrug compound is selected from the following structures: Preferred

[0026] In a more specific embodiment, the present invention provides the above-described pharmaceutical composition, wherein the precursor compound is compound 1 having the following structure:

[0027] In a more specific embodiment, the present invention provides the above-described pharmaceutical composition, wherein the radionuclide is selected from at least one of diagnostic radionuclides or therapeutic radionuclides;

[0028] Preferably, the diagnostic radionuclide is selected from... 68 Ga、 18 F, 99 mTc,89 Zr、 124 I, 76 Br、 43 Sc、 111 In、 45 Ti、 52 Mn, 59 Fe、 64 Cu、 94 mTc, 67 Ga、 71 / 72 / 74 As、 82m Rb or 86 Y;

[0029] Preferably, the therapeutic radionuclide is selected from... 177 Lu、 90 Y、 131 I, 153 Sm、 67 Cu、 89 Sr、 166 Ho、 177 Yb、 47 Sc、 186 / 188 Re、 212 / 213 Bi、 149 Pm, 212 Pb, 211 At、 223 Ra、 161 Tb, 225 Ac or 227 Th;

[0030] Preferably, the radionuclide is selected from... 68 Ga、 18 F, 89 Zr、 99 mTc or 177 Lu;

[0031] Preferably, the radioactive nuclide is 18 F; Preferably, the 18 F is a metal fluoride (preferably) 18 The precursor compound complexes with the form of FAl.

[0032] In a more specific embodiment, the present invention provides the above-described pharmaceutical composition, wherein the volumetric radioactivity of the radionuclide is about 1 mCi / mL to 200 mCi / mL, preferably about 2 mCi / mL to 100 mCi / mL, preferably about 5 mCi / mL to 65 mCi / mL, preferably about 6.8 mCi / mL to 62 mCi / mL; preferably about 10 mCi / mL to 65 mCi / mL, preferably about 10 mCi / mL to 62 mCi / mL; for example, about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 or 65 mCi / mL.

[0033] In a more specific embodiment, the present invention provides the above-described pharmaceutical composition, which further includes an osmotic pressure regulator; preferably, the osmotic pressure regulator is selected from sodium chloride, mannitol, glucose, dextran, and sucrose, and more preferably sodium chloride;

[0034] Preferably, the content of the osmotic pressure regulator is about 0.05 g / mL to 2 g / mL; more preferably about 0.1 g / mL to 1.5 g / mL; more preferably about 0.5 g / mL to 1 g / mL; more preferably about 0.8 g / mL to 1 g / mL, for example about 0.5 g / mL, 0.6 g / mL, 0.7 g / mL, 0.8 g / mL, 0.9 g / mL or 1 g / mL.

[0035] Preferably, the content of the osmotic pressure regulator is such that the osmotic pressure of the pharmaceutical composition is adjusted to about 200-350 mOsmol / kg, more preferably about 250-310 mOsmol / kg, and even more preferably about 280-310 mOsmol / kg; for example, about 250, about 260, about 270, about 280, about 285, about 290, about 295, about 300, about 305, or about 310 mOsmol / kg; more preferably about 300-310 mOsmol / kg.

[0036] Existing radiopharmaceutical compositions typically include stabilizers to ensure product stability. However, the addition of stabilizers may negatively impact the complexation of the radionuclide with the chelating agent, or may cause the stabilizer to precipitate from the solution due to limited solubility.

[0037] In a more specific embodiment, the stabilizer is selected from one or more of gentian acid or its salt, ascorbic acid or its salt, histidine, cysteine ​​or its salt, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, propylene glycol, glycerol, polyethylene glycol, polyvinyl alcohol, trehalose, povidone, nicotinamide, curcumin, and melatonin; preferably one or more of gentian acid or its salt and ascorbic acid or its salt.

[0038] In a more specific embodiment, the present invention provides the above-described pharmaceutical composition, wherein it does not contain one or more stabilizers selected from gentianic acid or its salts and ascorbic acid or its salts; preferably, it does not contain one or more stabilizers selected from gentianic acid or its salts, ascorbic acid or its salts, histidine, cysteine ​​or its salts, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, propylene glycol, glycerol, polyethylene glycol, polyvinyl alcohol, trehalose, povidone, nicotinamide, curcumin, and melatonin; preferably, it does not contain stabilizers.

[0039] In a more specific embodiment, the present invention provides the above-described pharmaceutical composition comprising the following components in amounts:

[0040] A complex formed by the complexation of a radionuclide and a precursor compound, wherein the volumetric radioactivity of the radionuclide is about 1 mCi / mL to 200 mCi / mL; preferably, the precursor compound is compound 1 as described in claim 4;

[0041] The osmotic pressure regulator is approximately 0.05 g / mL to 2 g / mL, preferably approximately 0.1 g / mL to 1.5 g / mL;

[0042] The remainder is water;

[0043] The pharmaceutical composition does not contain one or more stabilizers selected from gentianic acid or its salts and ascorbic acid or its salts;

[0044] Preferably,

[0045] The pharmaceutical composition comprises the following components in varying amounts:

[0046] Radionuclides 18 The complex formed by F and the precursor compound, wherein the volumetric radioactivity of the radionuclide is about 2 mCi / mL to 100 mCi / mL; preferably, the precursor compound is compound 1 as described in claim 4;

[0047] Osmotic pressure regulator: approximately 0.5 g / mL - 1 g / mL;

[0048] The remainder is water;

[0049] The pharmaceutical composition does not contain one or more stabilizers selected from gentian acid or its salts, ascorbic acid or its salts, histidine, cysteine ​​or its salts, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, propylene glycol, glycerol, polyethylene glycol, polyvinyl alcohol, trehalose, povidone, nicotinamide, curcumin, and melatonin.

[0050] Preferably,

[0051] The pharmaceutical composition comprises the following components in varying amounts:

[0052] Radionuclides 18 F and the complex formed by complexing compound 1 according to claim 4, wherein the volumetric radioactivity of the radionuclide is about 5 mCi / mL to 65 mCi / mL, preferably about 6.8 mCi / mL to 62 mCi / mL;

[0053] Sodium chloride is approximately 0.8-1 g / mL, preferably approximately 0.9 g / mL;

[0054] The remainder is water;

[0055] The pharmaceutical composition does not contain stabilizers;

[0056] Preferably, the 18 F is a metal fluoride (preferably) 18 The precursor compound complexes with the form of FAl.

[0057] In a more specific embodiment, the present invention provides the above-described pharmaceutical composition, wherein the water is water for injection.

[0058] In a more specific embodiment, the present invention provides the above-described pharmaceutical composition, wherein, optionally, residual solvent is included; preferably, residual solvent is almost entirely excluded; preferably, the volume fraction of residual solvent is less than about 15%, preferably less than about 12%, preferably less than about 10%, preferably less than about 5%, and more preferably less than about 5%, for example, less than about 4.5%, 4%, 3.7%, 3.5%, 3.6%, 3%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%; preferably, solvent residue is excluded.

[0059] Preferably, the solvent residue is ethanol and / or acetonitrile; ethanol is preferred.

[0060] Preferably, the volume fraction of the ethanol is less than about 10%, for example, less than about 9.5%, 9.1%, 9%, 8.5%, 8%, 7.5%, 75%, 6.5%, 6%, or 5.5%; more preferably less than about 5%, for example, less than about 4.5%, 4%, 3.7%, 3.6%, 3.5%, 3.4%, 3%, 2.5%, 2%, 1.6%, 1.5%, 1.4%, 1.3%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%.

[0061] Preferably, the acetonitrile content is less than about 0.5 mg / mL, for example, less than about 0.5 mg / mL, 0.45 mg / mL, 0.4 mg / mL, 0.35 mg / mL, 0.33 mg / mL, 0.3 mg / mL, 0.25 mg / mL, 0.2 mg / mL, 0.15 mg / mL, 0.1 mg / mL, 0.09 mg / mL, 0.08 mg / mL, 0.07 mg / mL, 0.06 mg / mL, 0.05 mg / mL, 0.04 mg / mL, 0.03 mg / mL, 0.02 mg / mL, 0.01 mg / mL, 0.004 mg / mL, 0.001 mg / mL, 0.0001 mg / mL, or 0.000078 mg / mL.

[0062] In a more specific embodiment, the present invention provides the above-described pharmaceutical composition, wherein the pharmaceutical composition is about 0.1-100 mL, preferably about 1-50 mL, more preferably about 1-30 mL, even more preferably about 5-30 mL, for example about 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 20 mL, 21 mL, 22 mL, 23 mL, 24 mL, 25 mL, 26 mL, 29 mL, or 30 mL.

[0063] In a more specific embodiment, the present invention provides the above-described pharmaceutical composition, wherein the pharmaceutical composition is ready for immediate use.

[0064] In a more specific embodiment, the present invention provides a method for preparing a pharmaceutical composition, comprising: a) reacting a radionuclide with a precursor compound to form a complex; preferably, mixing a solution containing the precursor compound with a solution containing the radionuclide to carry out the reaction;

[0065] Wherein, the precursor compound is as defined in this invention, and the radionuclide is as defined in this invention.

[0066] In a more specific embodiment, the present invention provides the above-described preparation method, wherein the radioactive nuclide is... 18 F, the reaction system in step a) also contains substances capable of reacting with... 18 The reaction of F produces a metal salt compound of metal fluoride (preferably a salt of divalent Zn, a salt of trivalent Fe, or a salt of trivalent Al, preferably aluminum chloride);

[0067] Preferably, the molar ratio of the metal salt compound to the precursor compound is about (0.05-1.0):1; more preferably about (0.1-0.7):1; more preferably about (0.2-0.5):1; more preferably about (0.25-0.45):1; more preferably about (0.28-0.45):1; for example, about 0.1:1, 0.15:1, 0.2:1, 0.25:1, 0.26:1, 0.266:1, 0.27:1, 0.285:1, 0.286:1, 0.29:1, 0.296:1, 0.3:1, 0.3 1:1, 0.319:1, 0.32:1, 0.325:1, 0.33:1, 0.333:1, 0.34:1, 0.35:1, 0.36:1, 0.37:1, 0.38:1, 0.39:1, 0.4:1, 0.41:1, 0.42:1, 0.43:1, 0.44:1, 0.444:1, 0.45:1, 0.46:1, 0.47:1, 0.48:1, 0.49:1, 0.5:1, 0.55:1, 0.6:1, 0.65:1, or 0.7:1;

[0068] Preferably, the molar amount of the metal salt compound is sufficient to... 18 F complete complexation.

[0069] In a more specific embodiment, the present invention provides the above preparation method, wherein the reaction temperature is about 45°C-100°C; preferably about 50°C-90°C; preferably about 55°C-85°C; preferably about 70°C-80°C; for example about 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C or 85°C; preferably about 75°C.

[0070] In a more specific embodiment, the present invention provides the above preparation method, wherein the molar amount of the precursor compound in the reaction system of step a) is: the radioactivity of the radionuclide is about 1 μmol:(100-10000) mCi; preferably about 1 μmol:(200-8000) mCi; preferably about 1 μmol:(400-7500) mCi, preferably about 1 μmol:(474-7111) mCi; preferably about 1 μmol:(400-5500) mCi, preferably about 1 μmol:(474-5185) mCi; preferably about 1 μmol:(600-5000) mCi, preferably about 1 μmol:(800-5000) mCi.

[0071] In a more specific embodiment, the present invention provides the above-described preparation method, wherein the content of the radionuclide in the reaction system of step a) is about 10 mCi / mL-1000 mCi / mL; preferably about 20 mCi / mL-700 mCi / mL; preferably about 35 mCi / mL-600 mCi / mL; preferably about 41.3 mCi / mL-516.1 mCi / mL; preferably about 30 mCi / mL-500 mCi / mL; preferably about 35 mCi / mL-470 mCi / mL; preferably about 41.3 mCi / mL-451.6 mCi / mL; preferably about 60 mCi / mL-500 mCi / mL; preferably about 70 mCi / mL-470 mCi / mL.

[0072] Preferably, the content of the precursor compound in the reaction system of step a) is about 0.03 μmol / mL to 0.2 μmol / mL; more preferably about 0.05 μmol / mL to 0.15 μmol / mL; more preferably about 0.07 μmol / mL to 0.12 μmol / mL; more preferably about 0.075 μmol / mL to 0.10 μmol / mL; more preferably about 0.08 μmol / mL to 0.09 μmol / mL; for example, about 0.05, 0.055, 0.06, 0.0625, 0.065 0.07, 0.0726, 0.075, 0.08, 0.0844, 0.085, 0.0871, 0.0894, 0.09, 0.091, 0.092, 0.093, 0.0931, 0.094, 0.095, 0.096, 0.097, 0.098, 0.099, 0.1, 0.102, 0.104, 0.109, 0.11, 0.12, 0.13, 0.14 or 0.15 μmol / mL; preferably about 0.0871 μmol / mL;

[0073] Preferably, the concentration of the precursor compound in the solution is about 0.05 μmol / mL to 0.15 μmol / mL; more preferably about 0.06 μmol / mL to 0.14 μmol / mL; more preferably about 0.07 μmol / mL to 0.14 μmol / mL; more preferably about 0.08 μmol / mL to 0.14 μmol / mL; more preferably about 0.08 to 0.12 μmol / mL; for example, about 0.05, 0.055, 0.06, 0.065, 0.07, 0.0 726, 0.075, 0.08, 0.085, 0.0865, 0.0871, 0.09, 0.091, 0.092, 0.093, 0.094, 0.095, 0.096, 0.097, 0.098, 0.099, 0.1, 0.102, 0.104, 0.107, 0.108, 0.109, 0.11, 0.12, 0.121, 0.129, 0.13, 0.135, 0.14 or 0.15 μmol / mL; preferably about 0.104 μmol / mL.

[0074] In a more specific embodiment, the present invention provides the above preparation method, wherein the reaction system in step a) further includes a solvent; preferably, the solvent is selected from one or more of acetonitrile, ethanol, DMSO and water, preferably acetonitrile and / or water;

[0075] Preferably, the solvent is selected from a combination of solvent A and solvent B, wherein solvent A is selected from one or more of acetonitrile, ethanol and DMSO (preferably acetonitrile), and solvent B is water;

[0076] Preferably, the volume ratio of solvent A to solvent B is about (1-12):1; more preferably about (2-10):1; more preferably about (3-7):1; more preferably about (3.5-7):1; for example, about 2:1, 2.5:1, 3:1, 3.1:1, 3.2:1, 3.3:1, 3.33:1, 3.4:1, 3.5:1, 3.6:1, 3.7:1, 3.8:1, 3.9 :1, 4:1, 4.1:1, 4.17:1, 4.2:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.1:1, 6.2:1, 6.25:1, 6.3:1, 6.4:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1 or 10:1; preferably about 4-4.5:1, for example about 4.17:1;

[0077] Preferably, the solvent in the solution containing the precursor compound includes one or more of acetonitrile, ethanol, and DMSO, preferably acetonitrile; preferably, it also includes water; preferably, the water in the solution containing the precursor compound accounts for less than about 10% of the total volume of the solvent, preferably less than about 8%, for example less than about 8%, 7%, 6%, or 5%, preferably about 1%-7% of the total volume of the solvent, preferably about 2%-6%, preferably about 2%-5%, preferably about 3%-5%, for example about 3.2%-4.8%; for example about 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5%;

[0078] Preferably, the solvent in the solution containing the radioactive nuclide includes water;

[0079] Preferably, the volume ratio of the solution containing the precursor compound to the solution containing the radionuclide is about (1-12):1; more preferably about (2-10):1; more preferably about (4-9):1; for example, about 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.1:1, 4.2:1, 4.3:1, 4.5:1, 5.0:1, 5.2:1, 5.5:1, 6.0:1, 6.2:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.3:1, 8.5:1, 8.7:1, 9:1, 9.5:1 or 10:1; preferably about 5.2:1.

[0080] In a more specific embodiment, the present invention provides the above preparation method, wherein the reaction system in step a) further includes a pH adjuster to make the pH value of the reaction system about 2-7; preferably about 2-8; preferably about 3-4;

[0081] Preferably, the pH adjuster is selected from alkaline pH adjusters and acidic pH adjusters; more preferably, it is an acidic pH adjuster.

[0082] Preferably, the acidic pH adjuster is selected from one or more of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, sodium dihydrogen phosphate, citric acid, citric acid, and lactic acid; more preferably, it is selected from one or more of hydrochloric acid, acetic acid, and phosphoric acid.

[0083] Preferably, the pH adjuster is acetic acid, and is preferably added in the form of an aqueous solution of acetic acid with a mass fraction of about 36%-37%.

[0084] Preferably, the solution containing the precursor compound contains a pH adjuster, and the pH adjuster is present in the reaction system after the mixing.

[0085] In a more specific embodiment, the present invention provides the above preparation method, wherein the reaction time is about 5 min to 30 min; preferably about 10 min to 20 min; preferably about 15 min.

[0086] In a more specific embodiment, the present invention provides the above preparation method, wherein the preparation method further includes: b) purifying the reaction solution after step a) to obtain a solution containing the complex, and then mixing the solution containing the complex with a diluent;

[0087] Preferably, the purification is performed using a C18 silica gel column;

[0088] Preferably, the purified eluent is ethanol;

[0089] Preferably, the diluent is an aqueous solution containing an osmotic pressure regulator, wherein the osmotic pressure regulator is as defined in claim 7; preferably, it is physiological saline.

[0090] Preferably, step b) further includes aseptically filtering the diluted solution; preferably using a sterile filter membrane; preferably, the pore size of the sterile filter membrane is 0.22 μm;

[0091] Preferably, the radionuclide in step a) is a purified radionuclide, preferably purified by a QMA column, and preferably the eluent for purification is an aqueous solution of salt and / or amino polyether K222 with a mass fraction of about 0.5 g / mL to 1 g / mL (preferably about 0.8 g / mL to 1 g / mL); preferably, the salt is selected from one or more of sodium chloride, NaHCO3 and K2CO3; preferably, the eluent is physiological saline.

[0092] Preferably, the reaction system or solution containing radionuclides in step a) further includes residual eluent solutes, such as salts and / or amino polyether K222; preferably, the salt is selected from one or more of sodium chloride, NaHCO3 and K2CO3, with sodium chloride being preferred.

[0093] In a more specific embodiment, the present invention provides a pharmaceutical formulation comprising the pharmaceutical composition of any one of claims 1-13; optionally, the pharmaceutical formulation further comprises a pharmaceutically acceptable carrier or excipient.

[0094] In a more specific embodiment, the present invention provides a pharmaceutical preparation obtained by the preparation method of the present invention.

[0095] In a more specific embodiment, the present invention provides the use of the pharmaceutical compositions or pharmaceutical preparations of the present invention in the preparation of reagents and / or medicaments for the diagnosis and / or treatment of one or more tumors or cells expressing carbonic anhydrase IX.

[0096] In a more specific embodiment, the present invention provides a pharmaceutical composition or pharmaceutical preparation of the present invention for the diagnosis and / or treatment of one or more tumors or cells expressing carbonic anhydrase IX.

[0097] In a more specific embodiment, the present invention provides a method for diagnosing and / or treating one or more tumors or cells expressing carbonic anhydrase IX, wherein the method comprises administering a pharmaceutical composition or pharmaceutical preparation of the present invention to a subject.

[0098] In a more specific embodiment, the tumor expressing carbonic anhydrase IX is selected from one or more of the following: kidney cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, melanoma, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head and neck cancer, astrocytoma, and oral cancer.

[0099] In a more specific embodiment, the diagnostic method is selected from optical imaging and / or radionuclide imaging; preferably, the radionuclide imaging is selected from PET imaging and / or SPECT imaging.

[0100] Preferably, the treatment is selected from radiotherapy and / or fluorescent surgical navigation to assist in surgery.

[0101] In a more specific embodiment, the present invention provides a method for imaging tissue expressing carbonic anhydrase IX, comprising administering the pharmaceutical composition or pharmaceutical preparation of the present invention to the tissue, and imaging the tissue after administration.

[0102] Preferably, the imaging is emission computed tomography, performed by positron emission tomography or single-photon emission computed tomography.

[0103] Example

[0104] The compounds and preparation methods of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of protection of the present invention. All technical solutions implemented based on the content of the present invention are covered within the scope of protection intended by the present invention.

[0105] Unless otherwise specified, the experimental methods used in the following examples are conventional methods in the art; the reagents, raw materials, instruments, equipment, etc. used in the following examples are all commercially available.

[0106] Example 1

[0107] Transfer 2.5-3 mL of acetonitrile, 45-50 μL of aluminum chloride hexahydrate aqueous solution / aluminum chloride aqueous solution (2 mmol / L), 24 μL (containing 200-300 μg) of NYM005 precursor aqueous solution and 40-50 μL of acetic acid solution (mass fraction 36%-37%) to a 10 mL reaction flask, and gently shake the reaction flask to mix thoroughly.

[0108] 18 F can be generated by a cyclotron. Irradiation was performed using a cyclotron (Sumitomo HM-10) at a current of 55 μA for 60 minutes, producing an activity of approximately 1.0-1.6 Ci. A certain amount (all or approximately 300 mCi) of the generated fluorine [18F] aqueous solution was taken, and its radioactivity was measured using an activity meter and recorded as the reaction activity value for the following experiment. The fluorine [18F] aqueous solution was added to a pretreated QMA column, followed by elution with 0.5 mL of physiological saline. The eluent flowed directly into the reaction flask, which was then capped with a rubber stopper.

[0109] Place the reaction flask at 75°C for 15 minutes. Then cool the reaction flask to room temperature.

[0110] Extract all of the reaction solution and add it to a 100 mL sterile open bottle containing 25 mL of sterile water for injection. In three separate applications, extract 10 mL of the diluted reaction solution onto the activated C18 column, discarding the eluent. Repeat this process four times, ensuring each application is dry. Rinse the C18 column with 30 mL of sterile water for injection and dry it, discarding the eluent. Slowly wash the C18 column with 1 mL of anhydrous ethanol, collecting the eluent in a product bottle, and then dilute with 10 mL–30 mL of physiological saline.

[0111] The solution in the product bottle was filtered through a sterile filter membrane with a pore size of 0.22 μm into the finished product bottle to obtain the desired solution. The radioactivity was measured using an activity meter to calculate the yield. The radiochemical purity was analyzed using Radio-HPLC.

[0112] Example 2

[0113] Transfer 2.5 mL of acetonitrile, 45 μL of 2 mM aluminum chloride hexahydrate aqueous solution (2 mmol / L), 24 μL of NYM005 precursor solution (containing 240 μg), and 45 μL of acetic acid solution (36%-37% by mass) to a 10 mL reaction flask and gently shake to mix thoroughly. Elute the QMA column with 0.5 mL of physiological saline using the aqueous solution of fluorine [18F] generated in the first stage of the cyclotron reaction. React in the reaction flask at 75 °C for 15 min. Cool the reaction flask to room temperature. After the reaction is complete, purify using a C18 column. Slowly wash the C18 column with 1 mL of anhydrous ethanol solution, collect the effluent into a product bottle, and then dilute with 28 mL of physiological saline. Obtain 29 mL of the desired product.

[0114] Table 1

[0115] Example 3

[0116] The product was prepared according to the method in Example 2, except that: after the reaction, the C18 column was slowly eluted with 1 mL of anhydrous ethanol solution, the effluent was collected into a product bottle, and then diluted with 10 mL of physiological saline. 11 mL of the desired product was obtained.

[0117] Example 4

[0118] This embodiment further examines the applicability of the preparation method of the present invention.

[0119] The amount of QMA eluent was changed, and other conditions were the same as in Example 3. The analysis results are shown in Table 2.

[0120] Table 2

[0121] Among them, the 18F non-complexing substances are those that complex with 18F after excluding the target product. As shown in Table 2, by changing the amount of QMA eluent (physiological saline) between 0.3 and 0.6 mL, the radiochemical purity of the target product can reach over 95%.

[0122] The amount of acetonitrile was changed, and other conditions were the same as in Example 3. The analysis results are shown in Table 3 below.

[0123] Table 3

[0124] As can be seen from Table 3, when the amount of acetonitrile is between 2 mL and 3 mL, the target product can be obtained with high purity and high yield.

[0125] The amount of aluminum chloride was changed, and other conditions were the same as in Example 3. The analysis results are shown in Table 4.

[0126] Table 4

[0127] As can be seen from Table 4, when the amount of aluminum chloride aqueous solution (2 mmol / L) is between 40 and 50 μL, the radiochemical purity of the target product can reach more than 95%.

[0128] The amount of precursor compound was changed, and other conditions were the same as in Example 3. The analytical results are shown in Table 5.

[0129] Table 5

[0130] As can be seen from Table 5, when the amount of the precursor NYM005 is between 200 and 300 μg, the radiochemical purity of the target product can reach over 95%.

[0131] The amount of glacial acetic acid was changed, and other conditions were the same as in Example 3. The experimental results are shown in Table 6.

[0132] Table 6

[0133] As can be seen from Table 6, when the amount of glacial acetic acid is between 5 and 20 μL, the radiochemical purity of the drug solution can reach over 95%.

[0134] Method for determining the pH of the reaction solution: After the reaction is completed and the drug solution is purified, take 1 mL of the solution, add 1 mL of sterile water for injection to dilute it, and then measure the pH.

[0135] The reaction temperature was changed, and other conditions were the same as in Example 3. The experimental results are shown in Table 7.

[0136] Table 7

[0137] As can be seen from Table 7, when the reaction temperature is between 55 and 85°C, the radiochemical purity of the drug solution can reach more than 95%, and the preferred reaction temperature is 75°C.

[0138] The reaction conditions were the same as in Example 3. Samples were taken and tested at different time points, and the experimental results are shown in Table 8 below.

[0139] Table 8

[0140] As can be seen from Table 8, when the reaction temperature is between 10 and 20 min, the radiochemical purity of the drug solution can reach over 95%.

[0141] It is evident that the preparation method of the drug solution of the present invention is simple, the conditions are mild, and it can achieve high radiochemical purity within a wide range of reaction conditions (time, AlCl3 dosage, solvent dosage, temperature, precursor dosage).

[0142] Example 5

[0143] Solvent residue experiment:

[0144] The drug solution was prepared under the following conditions, with the remaining conditions being the same as in Example 3. The residual solution was tested by GC, and the experimental results are shown in Table 9.

[0145] Table 9

[0146] As can be seen from Table 9, the product prepared by the method of the present invention has a low residual content of solvent.

[0147] Stability test:

[0148] The drug solution was prepared under the following conditions, with the remaining conditions the same as in Example 3. The product stability was tested at 30°C and 40°C, and the experimental results are shown in Tables 10 and 11.

[0149] Table 10

[0150] Table 11

[0151] As can be seen from Tables 10 and 11, the product of the present invention does not show significant change in purity and has good stability when placed at 30℃ and 40℃ for 6 or 8 hours.

[0152] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A pharmaceutical composition comprising a complex and water; in, The complex is a complex formed by the complexation of a radionuclide and a precursor compound; the precursor compound is a carbonic anhydrase IX targeting ligand linked to the chelating agent.

2. The pharmaceutical composition of claim 1, wherein, In the precursor compound, the portion of the carbonic anhydrase IX targeting ligand is selected from the following structures: Where n = 0 or 2; preferred 3. The pharmaceutical composition of claim 1 or 2, wherein, In the precursor compound, the chelating agent portion is selected from the following structures: Preferred 4. The pharmaceutical composition according to any one of claims 1-3, wherein, The precursor compound is compound 1, having the following structure:

5. The pharmaceutical composition according to any one of claims 1-4, wherein, The radionuclide is selected from at least one of diagnostic or therapeutic radionuclides; Preferably, the diagnostic radionuclide is selected from... 68 Ga、 18 F, 99 mTc, 89 Zr、 124 I, 76 Br、 43 Sc、 111 In、 45 Ti、 52 Mn, 59 Fe、 64 Cu、 94 mTc, 67 Ga、 71 / 72 / 74 As、 82m Rb or 86 Y; Preferably, the therapeutic radionuclide is selected from... 177 Lu、 90 Y、 131 I, 153 Sm、 67 Cu、 89 Sr、 166 Ho、 177 Yb、 47 Sc、 186 / 188 Re、 212 / 213 Bi、 149 Pm, 212 Pb, 211 At、 223 Ra、 161 Tb, 225 Ac or 227 Th; Preferably, the radionuclide is selected from... 68 Ga、 18 F, 89 Zr、 99 mTc or 177 Lu; Preferably, the radioactive nuclide is 18 F; Preferably, the 18 F is a metal fluoride (preferably) 18 The precursor compound complexes with the form of FAl.

6. The pharmaceutical composition according to any one of claims 1-5, wherein, The volumetric radioactivity of the radionuclide is about 1 mCi / mL to 200 mCi / mL, preferably about 2 mCi / mL to 100 mCi / mL, preferably about 5 mCi / mL to 65 mCi / mL, preferably about 6.8 mCi / mL to 62 mCi / mL; preferably about 10 mCi / mL to 65 mCi / mL, preferably about 10 mCi / mL to 62 mCi / mL; for example, about 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60 or 65 mCi / mL.

7. The pharmaceutical composition according to any one of claims 1-6, wherein, It also includes an osmotic pressure regulator; preferably, the osmotic pressure regulator is selected from sodium chloride, mannitol, glucose, dextran, and sucrose, with sodium chloride being the most preferred; Preferably, the content of the osmotic pressure regulator is about 0.05 g / mL to 2 g / mL; more preferably about 0.1 g / mL to 1.5 g / mL; more preferably about 0.5 g / mL to 1 g / mL; more preferably about 0.8 g / mL to 1 g / mL, for example about 0.5 g / mL, 0.6 g / mL, 0.7 g / mL, 0.8 g / mL, 0.9 g / mL or 1 g / mL.

8. The pharmaceutical composition according to any one of claims 1-7, wherein, It does not contain any stabilizer selected from gentian acid or its salts and ascorbic acid or its salts; preferably, it does not contain any stabilizer selected from gentian acid or its salts, ascorbic acid or its salts, histidine, cysteine ​​or its salts, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, propylene glycol, glycerol, polyethylene glycol, polyvinyl alcohol, trehalose, povidone, nicotinamide, curcumin, and melatonin; preferably, it does not contain any stabilizer.

9. The pharmaceutical composition of any one of claims 1-8, comprising the following components in amounts: A complex formed by the complexation of a radionuclide and a precursor compound, wherein the volumetric radioactivity of the radionuclide is about 1 mCi / mL to 200 mCi / mL; preferably, the precursor compound is compound 1 as described in claim 4; The osmotic pressure regulator is approximately 0.05 g / mL to 2 g / mL, preferably approximately 0.1 g / mL to 1.5 g / mL; The remainder is water; in, The pharmaceutical composition does not contain one or more stabilizers selected from gentianic acid or its salts and ascorbic acid or its salts; Preferably, The pharmaceutical composition comprises the following components in varying amounts: Radionuclides 18 The complex formed by F and the precursor compound, wherein the volumetric radioactivity of the radionuclide is about 2 mCi / mL to 100 mCi / mL; preferably, the precursor compound is compound 1 as described in claim 4; Osmotic pressure regulator: approximately 0.5 g / mL - 1 g / mL; The remainder is water; The pharmaceutical composition does not contain one or more stabilizers selected from gentian acid or its salts, ascorbic acid or its salts, histidine, cysteine ​​or its salts, methionine, selenomethionine, thiosulfate, maltose, inositol, benzyl alcohol, propylene glycol, glycerol, polyethylene glycol, polyvinyl alcohol, trehalose, povidone, nicotinamide, curcumin, and melatonin. Preferably, The pharmaceutical composition comprises the following components in varying amounts: Radionuclides 18 F and the complex formed by complexing compound 1 according to claim 4, wherein the volumetric radioactivity of the radionuclide is about 5 mCi / mL to 65 mCi / mL, preferably about 6.8 mCi / mL to 62 mCi / mL; Sodium chloride is approximately 0.8-1 g / mL, preferably approximately 0.9 g / mL; The remainder is water; The pharmaceutical composition does not contain stabilizers; Preferably, the 18 F is a metal fluoride (preferably) 18 The precursor compound complexes with the form of FAl.

10. The pharmaceutical composition of any one of claims 1-9, wherein, The water in question is water for injection.

11. The pharmaceutical composition according to any one of claims 1-10, wherein, Optionally includes residual solvent; preferably includes almost no residual solvent; preferably the volume fraction of residual solvent is less than about 15%, preferably less than about 12%, preferably less than about 10%, preferably less than about 5%, preferably less than about 5%, for example less than about 4.5%, 4%, 3.7%, 3.5%, 3.6%, 3%, 2.5%, 2%, 1.5%, 1%, 0.5%, 0.4%, 0.3%, 0.2% or 0.1%; preferably excludes residual solvent. Preferably, the solvent residue is ethanol and / or acetonitrile; ethanol is preferred. Preferably, the volume fraction of the ethanol is less than about 10%, for example, less than about 9.5%, 9.1%, 9%, 8.5%, 8%, 7.5%, 75%, 6.5%, 6%, or 5.5%; more preferably less than about 5%, for example, less than about 4.5%, 4%, 3.7%, 3.6%, 3.5%, 3.4%, 3%, 2.5%, 2%, 1.6%, 1.5%, 1.4%, 1.3%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%. Preferably, the acetonitrile content is less than about 0.5 mg / mL, for example, less than about 0.5 mg / mL, 0.45 mg / mL, 0.4 mg / mL, 0.35 mg / mL, 0.33 mg / mL, 0.3 mg / mL, 0.25 mg / mL, 0.2 mg / mL, 0.15 mg / mL, 0.1 mg / mL, 0.09 mg / mL, 0.08 mg / mL, 0.07 mg / mL, 0.06 mg / mL, 0.05 mg / mL, 0.04 mg / mL, 0.03 mg / mL, 0.02 mg / mL, 0.01 mg / mL, 0.004 mg / mL, 0.001 mg / mL, 0.0001 mg / mL, or 0.000078 mg / mL.

12. The pharmaceutical composition of any one of claims 1-11, wherein, The pharmaceutical composition is about 0.1-100 mL, preferably about 1-50 mL, more preferably about 1-30 mL, even more preferably about 5-30 mL, for example about 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, 10 mL, 11 mL, 12 mL, 13 mL, 14 mL, 15 mL, 20 mL, 21 mL, 22 mL, 23 mL, 24 mL, 25 mL, 26 mL, 29 mL or 30 mL.

13. The pharmaceutical composition of any one of claims 1-12, wherein, The pharmaceutical composition is ready for immediate use.

14. A method for preparing the pharmaceutical composition according to any one of claims 1-13, comprising: a) Reacts radioactive nuclides with precursor compounds to form complexes; Preferably, the solution containing the precursor compound is mixed with the solution containing the radioactive nuclide for the reaction; The precursor compound is as defined in any one of claims 1-4, and the radionuclide is as defined in claim 5.

15. The preparation method of claim 14, wherein, The radioactive nuclide is 18 F, the reaction system in step a) also contains substances capable of reacting with... 18 The reaction of F produces a metal salt compound of metal fluoride (preferably a salt of divalent Zn, a salt of trivalent Fe, or a salt of trivalent Al, preferably aluminum chloride); Preferably, the molar ratio of the metal salt compound to the precursor compound is about (0.05-1.0):1; more preferably about (0.1-0.7):1; more preferably about (0.2-0.5):1; more preferably about (0.25-0.45):1; more preferably about (0.28-0.45):1; for example, about 0.1:1, 0.15:1, 0.2:1, 0.25:1, 0.26:1, 0.266:1, 0.27:1, 0.285:1, 0.286:1, 0.29:1, 0.296:1, 0.3:1, 0.3 1:1, 0.319:1, 0.32:1, 0.325:1, 0.33:1, 0.333:1, 0.34:1, 0.35:1, 0.36:1, 0.37:1, 0.38:1, 0.39:1, 0.4:1, 0.41:1, 0.42:1, 0.43:1, 0.44:1, 0.444:1, 0.45:1, 0.46:1, 0.47:1, 0.48:1, 0.49:1, 0.5:1, 0.55:1, 0.6:1, 0.65:1, or 0.7:1; Preferably, the molar amount of the metal salt compound is sufficient to... 18 F complete complexation.

16. The preparation method according to claim 14 or 15, wherein, The reaction temperature is about 45°C-100°C; preferably about 50°C-90°C; preferably about 55°C-85°C; preferably about 70°C-80°C; for example, about 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C or 85°C; preferably about 75°C.

17. The preparation method according to any one of claims 14-16, wherein, The molar amount of the precursor compound in the reaction system of step a) is: the radioactivity of the radionuclide is about 1 μmol:(100-10000) mCi; preferably about 1 μmol:(200-8000) mCi; preferably about 1 μmol:(400-7500) mCi, preferably about 1 μmol:(474-7111) mCi; preferably about 1 μmol:(400-5500) mCi, preferably about 1 μmol:(474-5185) mCi; preferably about 1 μmol:(600-5000) mCi, preferably about 1 μmol:(800-5000) mCi.

18. The preparation method according to any one of claims 14-17, wherein, The concentration of radionuclides in the reaction system of step a) is approximately 10 mCi / mL to 1000 mCi / mL; preferably approximately 20 mCi / mL to 700 mCi / mL; preferably approximately 35 mCi / mL to 600 mCi / mL; preferably approximately 41.3 mCi / mL to 516.1 mCi / mL; preferably approximately 30 mCi / mL to 500 mCi / mL; preferably approximately 35 mCi / mL to 470 mCi / mL; preferably approximately 41.3 mCi / mL to 451.6 mCi / mL; preferably approximately 60 mCi / mL to 500 mCi / mL; preferably approximately 70 mCi / mL to 470 mCi / mL. Preferably, the content of the precursor compound in the reaction system of step a) is about 0.03 μmol / mL to 0.2 μmol / mL; more preferably about 0.05 μmol / mL to 0.15 μmol / mL; more preferably about 0.07 μmol / mL to 0.12 μmol / mL; more preferably about 0.075 μmol / mL to 0.10 μmol / mL; more preferably about 0.08 μmol / mL to 0.09 μmol / mL; for example, about 0.05, 0.055, 0.06, 0.0625, 0.065 0.07, 0.0726, 0.075, 0.08, 0.0844, 0.085, 0.0871, 0.0894, 0.09, 0.091, 0.092, 0.093, 0.0931, 0.094, 0.095, 0.096, 0.097, 0.098, 0.099, 0.1, 0.102, 0.104, 0.109, 0.11, 0.12, 0.13, 0.14 or 0.15 μmol / mL; preferably about 0.0871 μmol / mL; Preferably, the concentration of the precursor compound in the solution is about 0.05 μmol / mL to 0.15 μmol / mL; more preferably about 0.06 μmol / mL to 0.14 μmol / mL; more preferably about 0.07 μmol / mL to 0.14 μmol / mL; more preferably about 0.08 μmol / mL to 0.14 μmol / mL; more preferably about 0.08 μmol / mL to 0.12 μmol / mL; for example, about 0.05, 0.055, 0.06, 0.065, 0.07, 0.0 726, 0.075, 0.08, 0.085, 0.0865, 0.0871, 0.09, 0.091, 0.092, 0.093, 0.094, 0.095, 0.096, 0.097, 0.098, 0.099, 0.1, 0.102, 0.104, 0.107, 0.108, 0.109, 0.11, 0.12, 0.121, 0.129, 0.13, 0.135, 0.14 or 0.15 μmol / mL; preferably about 0.104 μmol / mL.

19. The preparation method according to any one of claims 14-18, wherein, The reaction system in step a) further includes a solvent; preferably, the solvent is selected from one or more of acetonitrile, ethanol, DMSO and water, preferably acetonitrile and / or water; Preferably, the solvent is selected from a combination of solvent A and solvent B, wherein solvent A is selected from one or more of acetonitrile, ethanol and DMSO (preferably acetonitrile), and solvent B is water; Preferably, the volume ratio of solvent A to solvent B is about (1-12):1; more preferably about (2-10):1; more preferably about (3-7):1; more preferably about (3.5-7):1; for example, about 2:1, 2.5:1, 3:1, 3.1:1, 3.2:1, 3.3:1, 3.33:1, 3.4:1, 3.5:1, 3.6:1, 3.7:1, 3.8:1, 3.9 :1, 4:1, 4.1:1, 4.17:1, 4.2:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.1:1, 6.2:1, 6.25:1, 6.3:1, 6.4:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1 or 10:1; preferably about 4-4.5:1, for example about 4.17:1; Preferably, the solvent in the solution containing the precursor compound includes one or more of acetonitrile, ethanol, and DMSO, preferably acetonitrile; preferably, it also includes water; preferably, the water in the solution containing the precursor compound accounts for less than about 10% of the total volume of the solvent, preferably less than about 8%, for example less than about 8%, 7%, 6%, or 5%, preferably about 1%-7% of the total volume of the solvent, preferably about 2%-6%, preferably about 2%-5%, preferably about 3%-5%, for example about 3.2%-4.8%; for example about 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, or 5%; Preferably, the solvent in the solution containing the radioactive nuclide includes water; Preferably, the volume ratio of the solution containing the precursor compound to the solution containing the radionuclide is about (1-12):1; more preferably about (2-10):1; more preferably about (4-9):1; for example, about 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.1:1, 4.2:1, 4.3:1, 4.5:1, 5.0:1, 5.2:1, 5.5:1, 6.0:1, 6.2:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.3:1, 8.5:1, 8.7:1, 9:1, 9.5:1 or 10:1; preferably about 5.2:

1.

20. The preparation method according to any one of claims 14-19, wherein, The reaction system in step a) also includes a pH adjuster to make the pH of the reaction system about 2-7; preferably about 2-8; preferably about 3-4; Preferably, the pH adjuster is selected from alkaline pH adjusters and acidic pH adjusters; more preferably, it is an acidic pH adjuster. Preferably, the acidic pH adjuster is selected from one or more of hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, sodium dihydrogen phosphate, citric acid, citric acid, and lactic acid; more preferably, it is selected from one or more of hydrochloric acid, acetic acid, and phosphoric acid. Preferably, the pH adjuster is acetic acid, and is preferably added in the form of an aqueous solution of acetic acid with a mass fraction of about 36%-37%. Preferably, the solution containing the precursor compound contains a pH adjuster, and the pH adjuster is present in the reaction system after the mixing.

21. The preparation method according to any one of claims 14-20, wherein, The reaction time is approximately 5 min to 30 min; preferably approximately 10 min to 20 min; preferably approximately 15 min.

22. The preparation method according to any one of claims 14-21, wherein, The preparation method further includes: b) purifying the reaction solution after step a) to obtain a solution containing the complex, and then mixing the solution containing the complex with a diluent; Preferably, the purification is performed using a C18 silica gel column; Preferably, the purified eluent is ethanol; Preferably, the diluent is an aqueous solution containing an osmotic pressure regulator, wherein the osmotic pressure regulator is as defined in claim 7; preferably, it is physiological saline. Preferably, step b) further includes aseptically filtering the diluted solution; preferably using a sterile filter membrane; preferably, the pore size of the sterile filter membrane is 0.22 μm; Preferably, the radionuclide in step a) is a purified radionuclide, preferably purified by a QMA column, and preferably the eluent for purification is an aqueous solution of salt and / or amino polyether K222 with a mass fraction of about 0.5 g / mL to 1 g / mL (preferably about 0.8 g / mL to 1 g / mL); preferably, the salt is selected from one or more of sodium chloride, NaHCO3 and K2CO3; preferably, the eluent is physiological saline. Preferably, the reaction system or solution containing radionuclides in step a) further includes residual eluent solutes, such as salts and / or amino polyether K222; preferably, the salt is selected from one or more of sodium chloride, NaHCO3 and K2CO3, with sodium chloride being preferred.

23. A pharmaceutical preparation comprising the pharmaceutical composition of any one of claims 1-13; optionally, the pharmaceutical preparation further comprising a pharmaceutically acceptable carrier or excipient.

24. A pharmaceutical preparation, which is prepared by any one of the methods of claims 14-22.

25. Use of the pharmaceutical composition of any one of claims 1-13 or the pharmaceutical preparation of claim 23 or 24 in the preparation of reagents and / or pharmaceuticals for the diagnosis and / or treatment of one or more tumors or cells expressing carbonic anhydrase IX.

26. The pharmaceutical composition of any one of claims 1-13 or the pharmaceutical preparation of claim 23 or 24, for the diagnosis and / or treatment of one or more tumors or cells expressing carbonic anhydrase IX.

27. A method for diagnosing and / or treating one or more tumors or cells expressing carbonic anhydrase IX, wherein, The method is to administer to a subject the pharmaceutical composition of any one of claims 1-13 or the pharmaceutical preparation of claim 23 or 24.

28. The use of claim 25, or the pharmaceutical composition or formulation of claim 26, or the method of claim 27, wherein, The tumors expressing carbonic anhydrase IX are selected from one or more of the following: kidney cancer, lung cancer, colorectal cancer, gastric cancer, pancreatic cancer, melanoma, breast cancer, cervical cancer, bladder cancer, ovarian cancer, brain cancer, head and neck cancer, astrocytoma, and oral cancer.

29. The use of claim 25, or the pharmaceutical composition or formulation of claim 26, or the method of claim 27, wherein, The diagnostic method is selected from optical imaging and / or radionuclide imaging; preferably, the radionuclide imaging is selected from PET imaging and / or SPECT imaging. Preferably, the treatment is selected from radiotherapy and / or fluorescent surgical navigation to assist in surgery.

30. A method for imaging tissues expressing carbonic anhydrase IX, wherein, This includes administering the pharmaceutical composition of any one of claims 1-13 or the pharmaceutical formulation of claim 23 or 24 to the tissue, and imaging the tissue after administration; Preferably, the imaging is emission computed tomography, performed by positron emission tomography or single-photon emission computed tomography.

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