WO2023155454A1 - 碳酸酐酶ix靶向放射性诊疗药物及其制备方法 - Google Patents

碳酸酐酶ix靶向放射性诊疗药物及其制备方法 Download PDF

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WO2023155454A1
WO2023155454A1 PCT/CN2022/125512 CN2022125512W WO2023155454A1 WO 2023155454 A1 WO2023155454 A1 WO 2023155454A1 CN 2022125512 W CN2022125512 W CN 2022125512W WO 2023155454 A1 WO2023155454 A1 WO 2023155454A1
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group
compound
acid
pharmaceutically acceptable
solvate
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French (fr)
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方鹏
虞善友
朱文佳
霍力
颜成龙
伍维思
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无锡诺宇医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of medicine, specifically, the present invention relates to carbonic anhydrase (CA) IX targeted radiotherapy medicine and its preparation method, more specifically, the present invention relates to formula (I) or formula (II) compound or its pharmaceutical Acceptable salts, esters or solvates, complexes, pharmaceutical compositions and uses thereof.
  • CA carbonic anhydrase
  • Renal cell carcinoma is the most common renal neoplasm. Among cases of RCC, the clear cell subtype (ccRCC) is the most prevalent, accounting for up to 70% of RCC. Common in ccRCC is the loss of the Von Hippel-Lindau (VHL) tumor suppressor gene. Loss of VHL in turn leads to overexpression of carbonic anhydrase IX (CAIX) (Bragmaier et al., 2004, CAIX is a membrane-associated enzyme responsible for catalyzing the reversible hydration of carbon dioxide to bicarbonate anion and protons. Overexpression of CAIX has % of ccRCC tumor samples, making it a useful biomarker for this disease.
  • VHL Von Hippel-Lindau
  • CAIX has limited expression in normal tissues and organs except the gastrointestinal tract, gallbladder and pancreatic duct. There are no reports demonstrating CAIX expression in normal renal parenchyma or benign renal masses. The feasibility of non-invasive diagnosis of ccRCC based on CAIX expression has been demonstrated with the radiolabeled antibody G250.
  • antibodies as molecular imaging agents suffer from pharmacokinetic limitations, including slow blood and non-target tissue clearance (typically 2 to 5 days or longer) and nonspecific organ uptake.
  • Low molecular weight (LMW) agents demonstrate faster pharmacokinetics and higher specificity signals within a clinically convenient time after administration. They also offer site-specific radiolabelling, typically through a wider range of chemistries and radionuclides, and can offer shorter paths to regulatory agency approval.
  • the present invention proposes a compound or a pharmaceutically acceptable salt, ester or solvate thereof, the structure of which is shown in formula (I),
  • X is an optionally substituted 5-6 membered cycloalkyl, heterocyclyl, diazolyl, triazolyl or amido;
  • Y is Optionally substituted -COOH, Optionally substituted -OH, -CH(CH 3 )OH, water-soluble amino acid, chelating group or fluorescent group;
  • Z is H, a chelating group or a fluorescent group
  • At least one of Y and Z is a chelating group or a fluorescent group
  • L 1 , L 2 , and L 3 are respectively selected from polyethylene glycol chains, hydrophilic amino acid chains, carbon chains or -(CH 2 )nCONH-;
  • R 1 is selected from 5-12 membered heteroaryls substituted by sulfonic acid amino groups
  • n is an integer between 1 and 6.
  • the present invention proposes a compound or a pharmaceutically acceptable salt, ester or solvate thereof, the structure of which is shown in formula (I),
  • X is selected from 5-6 membered heterocyclic group, diazolyl, triazolyl and amido;
  • Y selected from -OH, -CH(CH 3 )OH, water-soluble amino acids, chelating groups and fluorescent groups;
  • Z is selected from H, a chelating group and a fluorescent group
  • L 1 , L 2 , and L 3 are respectively selected from polyethylene glycol chains, hydrophilic amino acid chains, and carbon chains;
  • R 1 is selected from a 5-12 membered heteroaryl group obtained by a sulfonic acid amino group.
  • the above-mentioned polyethylene glycol chain is a chain formed by one or more polyethylene glycol units (-O-(CH 2 ) 2 -O-), such as 1, 2, 3, 4 , 5, 6, 7 or 8 polyethylene glycol units (-O-(CH 2 ) 2 -O-) chains, and the remaining variables are as defined in the present invention.
  • the above-mentioned hydrophilic amino acid chain is a chain formed by condensation of one or more identical or different hydrophilic amino acids, such as 1, 2, 3, 4, 5, 6, 7 or 8
  • a chain formed by the condensation of hydrophilic amino acids which is a general term for amino acids with highly hydrophilic side chains, such as hydrophilic amino acids selected from threonine (Thr), serine (Ser), semi Cystine (Cys), Asparagine (Asn), Glutamine (Gln), Tyrosine (Tyr), Lysine (Lys), Arginine (Arg), Histidine (His), Tian Aspartic acid (Asp) or glutamic acid (Glu), the remaining variables are as defined herein.
  • the above-mentioned carbon chain refers to a carbon chain formed by one or more substituted or unsubstituted linear or branched alkyl groups, such as 1, 2, 3, 4, 5, 6 , substituted or unsubstituted straight-chain alkyl or branched-chain alkyl consisting of 7 or 8 carbon atoms, and the rest of the variables are as defined in the present invention.
  • the present invention also proposes a compound or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that its structure is shown in formula (II),
  • X is a 5-6 membered heterocyclic group, a cycloalkyl group, a diazolyl group, a triazolyl group or an amido group;
  • Y' is Optionally substituted -COOH, Optionally substituted -OH, -CH(CH 3 )OH, water-soluble amino acid, chelating group or fluorescent group;
  • Z is H, a chelating group or a fluorescent group
  • At least one of Y' and Z is a chelating group or a fluorescent group.
  • the present invention also proposes a compound or a pharmaceutically acceptable salt, ester or solvate thereof, characterized in that its structure is shown in formula (II),
  • X is selected from optionally substituted 5-6 membered heterocyclic groups, diazolyl, triazolyl and amido groups;
  • Y selected from -OH, -CH(CH 3 )OH, water-soluble amino acids, chelating groups and fluorescent groups;
  • Z is selected from H, a chelating group or a fluorescent group.
  • the above-mentioned chelating group is selected from 1,4,7,10-tetraazacyclododecane-N,N ⁇ ,N ⁇ ,N ⁇ ,-tetraacetic acid, 1 ,4,7-Triazacyclononane-1,4,7-triacetic acid, 2-(4,7-bis(carboxymethyl)-1,4,7-triazononon-1-yl) Glutaric acid, 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)glutaric acid, 1,4,7- Triazacyclononane phosphinic acid, 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2 -carboxymethyl)phosphinic acid], N'- ⁇ 5-[acetyl (hydroxyl)amino]pentyl ⁇ -N-[
  • the above-mentioned fluorescent groups are selected from anthocyanin fluorescent dyes, including non-sulfonated cyanine dyes and sulfonated cyanine dyes, and the remaining variables are as defined in the present invention.
  • the anthocyanin fluorescent dye is selected from Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Cy7.5, sulfonated-Cy3, sulfonated-Cy5 or sulfonated-Cy7 or ICG, etc., and the remaining variables are as defined in the present invention.
  • the above-mentioned fluorescent groups are selected from
  • the present invention also proposes a compound or a pharmaceutically acceptable salt, ester or solvate thereof, the structure of which is selected from the following one:
  • the present invention also proposes a compound.
  • the compound is covalently formed by the aforementioned compound or a pharmaceutically acceptable salt, ester or solvate thereof and radionuclide or non-radioactive element.
  • the radionuclide is selected from 68 Ga, 18 F, 99m Tc, 89 Zr, 111 In, 45 Ti, 59 Fe, 64 Cu, 94m Tc, 67 Ga, 71/72/74 As, 43/44 Sc, 82m Rb, 52 Mn, 86 Y, 125 I, 124 I, 76 Br, 177 Lu, 90 Y, 131 I, 153 Sm, 67 Cu, 89 Sr, 137 Cs, 166 Ho, 177 Yb, 105 Rh, 186/188 Re, 47 Sc, 212/213 Bi, 225 Ac, 212 Pb, 149 Pm, 211 At, 223 Ra and 227 Th.
  • the radionuclide is selected from131I .
  • the labeling site is on the phenolic hydroxyl group of tyrosine, and it can be labeled with other nuclides (such as 68 Ga) at the same time, and at the same time realize the diagnostic and therapeutic functions on one molecule.
  • the non-radioactive element is selected from Ga, Fe and Gd.
  • the radionuclide is selected from18F .
  • the radionuclide 18 F complex is formed by radioactive isotope aluminum fluoride.
  • the present invention also proposes a compound.
  • the structure of the compound is selected from one of the following:
  • the present invention also proposes a pharmaceutical composition.
  • the pharmaceutical composition comprises the aforementioned compound, or a pharmaceutically acceptable salt, ester or solvate thereof, and pharmaceutically acceptable carriers, excipients and the like.
  • the present invention also proposes the above-mentioned compound, or its pharmaceutically acceptable salt, ester or solvate, or the above-mentioned pharmaceutical composition in preparation for diagnosis and/or treatment Use of one or more tumors, cancers or cells expressing carbonic anhydrase IX in a reagent and/or a medicament.
  • the above diagnostic modalities are selected from optical imaging and/or nuclear imaging.
  • the aforementioned diagnostic modality is selected from fluorescence imaging, PET imaging and/or SPECT imaging.
  • the above-mentioned treatment is selected from radiotherapy and/or assisted surgery with fluoroscopic surgical navigation.
  • the aforementioned tumors and cancers are selected from renal cancer, glioma and other solid tumors and/or their metastatic lesions.
  • the present invention also proposes the aforementioned compound or its pharmaceutically acceptable salt, ester or solvate or the aforementioned pharmaceutical composition for diagnosing and/or treating the expression of carbonic anhydride Tumors, cancers or cells of enzyme IX.
  • the present invention also proposes the compound or its pharmaceutically acceptable salt, ester or solvate or the aforementioned pharmaceutical composition for diagnosing and/or treating renal cancer, brain Glioma and other solid tumors and/or their metastases.
  • the present invention also proposes a method for diagnosing and/or treating tumors, cancers or cells expressing carbonic anhydrase IX.
  • a pharmaceutically acceptable dose of the aforementioned compound or a pharmaceutically acceptable salt, ester or solvate thereof or the aforementioned pharmaceutical composition is administered to the patient.
  • the related diseases expressing carbonic anhydrase IX are kidney cancer, glioma and other solid tumors and/or their metastatic lesions.
  • the present invention also proposes a kit.
  • the kit comprises the aforementioned compound, or a pharmaceutically acceptable salt, ester or solvate thereof, or the aforementioned pharmaceutical composition.
  • the kit further comprises pharmaceutically acceptable carriers and excipients, and other variables are as defined in the present invention.
  • the aforementioned pharmaceutically acceptable carrier and adjuvant include sterile water for injection, acetic acid/sodium acetate buffer solution and sodium ascorbate.
  • the kit is prepared by the following method:
  • all the above-mentioned solutions are carried out under a clean bench with a grade C overall and a grade A part.
  • the present invention also proposes the aforementioned kit for diagnosing and/or treating one or more tumors and cancers expressing carbonic anhydrase IX.
  • the form of diagnosis is selected from optical imaging and/or nuclear imaging.
  • the aforementioned diagnostic modality is selected from fluorescence imaging, PET imaging and/or SPECT imaging.
  • the above-mentioned treatment is selected from radiotherapy and/or assisted surgery with fluoroscopic surgical navigation.
  • the aforementioned tumors and cancers are selected from renal cancer, glioma and other solid tumors and/or their metastatic lesions.
  • the present invention has at least one of the following advantages and effects relative to the prior art:
  • the synthetic raw materials of the compound of the present invention are easier to obtain, the synthetic process is simpler, and the yield is high.
  • the compound of the present invention adopts water-soluble amino acid, which has a simple molecular structure and small molecular weight, which is beneficial to the removal of the molecule in normal tissues and organs, greatly increasing the internal irradiation dose of patients in clinical application, and at the same time, the process is simpler.
  • amide bonds and amino acids are mainly used, so that the molecule can be synthesized using polypeptide solid-phase synthesis technology.
  • CMC chemical composition production and control
  • the present invention combines the radionuclide chelating group with larger molecular weight and the carbonic anhydrase IX target targeting group together to realize multiple functions on one molecule, and according to the current non-clinical According to the results of clinical experiments, the molecule has a good effect in radiodiagnostic tracing (PET/CT or SPECT/CT scanning), and the molecule has good safety.
  • the structure of the compound of the present invention further expands the suitable fluorescent group, which can realize fluorescence imaging and further assist doctors in fluorescent surgery navigation (after the fluorescent group is targeted to the tumor with the molecule, the tumor will bring Fluorescence, normal tissue does not have fluorescence, doctors can easily distinguish healthy tissue from tumor tissue during surgery, greatly improving the surgical effect).
  • the compounds of the present invention can be optionally substituted by one or more substituents, such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds.
  • substituents such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds.
  • substituents such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds.
  • substituents such as the above general formula compounds, or as specific examples in the examples, subclasses, and included in the present invention A class of compounds.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), Isopropyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH(CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2 -Butyl (-C(CH 3 ), 2-
  • alkyl and its prefix “alk” are used herein to include straight and branched saturated carbon chains.
  • alkylene is used herein to denote a saturated divalent hydrocarbon radical obtained by elimination of two hydrogen atoms from a linear or branched saturated hydrocarbon, examples of which include, but are not limited to, methylene, ethylene , Hypoisopropyl and so on.
  • cycloalkyl refers to a monocyclic, bicyclic or tricyclic ring system having one or more points of attachment to the rest of the molecule, saturated, containing from 3 to 12 ring carbon atoms.
  • cycloalkyl is a ring system containing 3-10 ring carbon atoms; in other embodiments, cycloalkyl is a ring system containing 3-8 ring carbon atoms; in some other embodiments, cycloalkyl is a ring system containing 3-6 ring carbon atoms; in some other embodiments, the cycloalkyl group is a ring system containing 5-6 ring carbon atoms; and the cycloalkyl group can be independently unsubstituted or One or more substituents described in the present invention are substituted.
  • aryl can be used alone or as a part of “aralkyl”, “aralkoxy” or “aryloxyalkyl” and represents monocyclic, bicyclic and tricyclic rings containing 6-14 ring members in total. Ring carbocyclic ring systems wherein at least one ring system is aromatic, wherein each ring system contains 3-7 membered rings and has one or more points of attachment to the rest of the molecule.
  • aryl may be used interchangeably with the term “aromatic ring”, eg aromatic rings may include phenyl, naphthyl and anthracenyl.
  • heteroaryl can be used alone or as a part of “heteroarylalkyl” or “heteroarylalkoxy” to represent monocyclic, bicyclic and tricyclic ring systems containing 5-14 ring members in total, Wherein at least one ring system is aromatic, and at least one ring system contains one or more heteroatoms, wherein the heteroatoms have the meaning described in the present invention, wherein each ring system contains 3-7 membered rings, and there is one or Multiple attachment points connect to the rest of the molecule.
  • heteroaryl may be used interchangeably with the terms “heteroaromatic ring” or “heteroaromatic”.
  • aromatic heterocycles include, but are not limited to, the following monocycles: 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- Imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazolyl- 5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, Pyridazinyl (such as 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (such as 5-tetrazolyl), triazolyl (such as 2-triazolyl and 5-triazoly
  • halogen denotes F, Cl, Br and I.
  • each independently is and “... and each independently are” used throughout this article are interchangeable and should be interpreted in a broad sense. It can mean that in different groups, the specific options expressed by the same symbols do not affect each other, and it can also mean that in the same group, the specific options expressed by the same symbols do not affect each other , such as the structure and structure The specific options of R 6 in the two are not affected by each other. At the same time, if multiple R 6 appear in the same structure, the specific options of multiple R 6 do not affect each other, that is, the specific options of R 6 can be the same, or Can be different.
  • Stereochemistry and use of conventions in the present invention are generally referred to in the following documents: S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S. ., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
  • the compounds of the present invention may contain asymmetric centers or chiral centers and thus exist as different stereoisomers. All stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers, atropisomers and mixtures thereof, such as racemic mixtures, form part of the invention .
  • optically active compounds that is, they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D, L or R, S are used to denote the absolute configuration of the molecular chiral center.
  • the prefixes d, l or (+), (-) are used to name the symbol of the compound's plane polarized light rotation, (-) or l means that the compound is left-handed, and the prefix (+) or d means that the compound is right-handed.
  • the chemical structures of these stereoisomers are the same, but their three-dimensional structures are different.
  • a particular stereoisomer may be an enantiomer, and a mixture of isomers is often referred to as an enantiomeric mixture.
  • racemic mixture A 50:50 mixture of enantiomers is known as a racemic mixture or racemate, which can result in no stereoselectivity or stereospecificity during a chemical reaction.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomers, devoid of optical activity.
  • tautomer or "tautomeric form” means that isomers of structures of different energies can be interconverted through a low energy barrier.
  • proton tautomers ie, prototropic tautomers
  • Atomic (valency) tautomers include interconversions of rearranged bonding electrons.
  • the "pharmaceutically acceptable salt” used in the present invention refers to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66, 1-19, 1977.
  • Pharmaceutically acceptable non-toxic acid-formed salts include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates , and organic acid salts, such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or by other methods described in books and literature such as ion exchange Come get these salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, cyclopentylpropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3 - Phenylpropionate
  • Salts obtained with appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the present invention also contemplates the quaternary ammonium salts of any compound containing an N group.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Pharmaceutically acceptable salts further include suitable, non-toxic ammonium/quaternary ammonium salts and counterion-forming amine cations such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 sulfonates and aromatic sulfonates.
  • suitable, non-toxic ammonium/quaternary ammonium salts and counterion-forming amine cations such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1 -8 sulfonates and aromatic sulfonates.
  • a “solvate” of the present invention refers to an association of one or more solvent molecules with a compound of the present invention.
  • Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, aminoethanol.
  • hydrate refers to an association of solvent molecules with water.
  • treating may include reversing, alleviating, inhibiting the development of, preventing or reducing the disease or the condition to which the term applies or one or more symptoms or manifestations of the disease or disorder .
  • Prevention means not causing aggravation of a disease, disorder, symptom or manifestation or severity. Accordingly, the presently disclosed plurality of compounds can be administered prophylactically to prevent or reduce the occurrence or recurrence of the disease or condition.
  • any disease or disease refers to all diseases or diseases that can be slowed down, interrupted, prevented, controlled or stopped, but does not necessarily mean that the symptoms of all diseases or diseases disappear completely, which also includes Prophylactic treatment of said symptoms, especially in patients predisposed to such diseases or disorders.
  • ameliorating the disease or condition ie slowing or arresting or alleviating the development of the disease or at least one clinical symptom thereof.
  • treating refers to alleviating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient.
  • treating refers to modulating a disease or condition either physically (eg, stabilizing a perceived symptom) or physiologically (eg, stabilizing a parameter of the body), or both. In other embodiments, “treating” refers to preventing or delaying the onset, development or worsening of a disease or condition.
  • terapéuticaally effective amount or “therapeutically effective dose” as used in the present invention refers to an amount capable of eliciting a biological or medical response (such as reducing or inhibiting enzyme or protein activity, or improving symptoms, relieving symptoms, slowing down or delaying disease) in an individual. development, or prevention of disease, etc.) amount of the compound of the present invention.
  • the term "therapeutically effective amount” refers to an amount effective when a compound of the invention is administered to an individual to: (1) at least partially alleviate, inhibit, prevent and/or ameliorate (i) mediated by carbonic anhydrase IX, or (ii) associated with carbonic anhydrase IX activity, or (iii) a condition or disease characterized by abnormal activity of carbonic anhydrase IX; or (2) reduces or inhibits carbonic anhydrase the activity of enzyme IX; or (3) reducing or inhibiting the expression of carbonic anhydrase IX.
  • the term "therapeutically effective amount” refers to at least partially reducing or inhibiting the activity of carbonic anhydrase IX when administered to cells, or organs, or non-cellular biological substances, or media; or at least partially An amount of a compound of the invention effective to reduce or inhibit the expression of carbonic anhydrase IX.
  • administering and “administering” a compound as used in the present invention should be understood as providing a compound of the invention or a salt, ester or solvate of a compound of the invention to an individual in need thereof. It should be recognized that those skilled in the art can treat diseases currently suffering from carbonic anhydrase IX expression, such as renal cancer, glioma and other solid tumors and/or their metastatic lesions, by using an effective amount of the compound of the present invention.
  • DOTA stands for 1,4,7,10-tetraazacyclododecane-N,N ⁇ ,N ⁇ ,N ⁇ ,-tetraacetic acid
  • NOTA stands for 1,4,7-triazacyclononane -1,4,7-triacetic acid
  • NODAGA stands for 2-(4,7-bis(carboxymethyl)-1,4,7-triazonon-1-yl)glutaric acid
  • DOTAGA stands for 2-( 4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)glutaric acid
  • TRAP stands for 1,4,7-triazacyclononane Alkylphosphinic acid
  • NOPO stands for 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphinic acid]-4,7-bis[methyl(2-carboxymethyl) base) phosphinic acid]
  • DFO represents N'- ⁇ 5-[acetyl
  • the structure of the sulfonated-Cy7 fluorescent group is as follows
  • Fig. 1 is the LC-MS spectrogram of the NYM005 molecule according to the embodiment of the present invention
  • Fig. 2 is the HPLC spectrogram of the NYM005 molecule according to the embodiment of the present invention.
  • Fig. 3 is a diagram showing the purity analysis results of radioactive TLC scanning of 68 Ga-NYM005 molecules according to an embodiment of the present invention
  • Fig. 4 is a pathological slice image according to an embodiment of the present invention, wherein the upper image is a HE pathological slice lesion image, and the lower image is a slice imaging image;
  • Figure 5 is a PET/CT image of the 68 Ga-NYM005 drug in the 786-O tumor-bearing mouse model according to an embodiment of the present invention, where the arrow is the tumor;
  • Fig. 6 is a PET/CT image of the 68 Ga-NYM005 drug in the OS-RC-2 tumor-bearing mouse model according to an embodiment of the present invention, where the arrow is the tumor;
  • Fig. 7 is a PET/CT scanning tissue distribution and targeting imaging results of 68Ga -NYM005 drug in 786-O tumor-bearing mouse model according to an embodiment of the present invention, where the arrow is the tumor;
  • Figure 8 is a graph showing the results of competitive inhibition of 68Ga -NYM005 on the 786-O tumor-bearing mouse model according to an embodiment of the present invention, where the arrow is the tumor;
  • Fig. 9 is the blood drug concentration-time graph of the mouse according to the embodiment of the present invention.
  • Fig. 10 is a PET/CT imaging result of 68 Ga-NYM005 in HT29, PC3, U87 tumor-bearing mouse models according to an embodiment of the present invention, where the arrow is the tumor;
  • Figure 11 is a PET/CT imaging result of 68 Ga-NYM005 on the HCT116 tumor-bearing mouse model according to an embodiment of the present invention, where the arrow is the tumor;
  • Fig. 12 is the body weight change figure of the mouse according to the embodiment of the present invention.
  • Fig. 13 is the clinical PET/CT imaging result of 68 Ga-NYM005 fluorescent molecular scientific research according to the embodiment of the present invention.
  • Fig. 14 is the LC-MS spectrogram of NYM034 molecule according to the embodiment of the present invention.
  • Fig. 15 is the HPLC spectrogram of NYM034 molecule according to the embodiment of the present invention.
  • Fig. 16 is a graph showing the purity analysis results of 68 Ga-NYM034 molecules according to an embodiment of the present invention by radioactive TLC scanning;
  • Figure 17 is a PET/CT imaging result of 68Ga -NYM034 on the 786-O, OS-RC-2 tumor-bearing mouse model according to an embodiment of the present invention, where the arrow is the tumor;
  • Fig. 18 is the LC-MS spectrogram of NYM035 molecule according to the embodiment of the present invention.
  • Fig. 19 is the HPLC spectrogram of NYM035 molecule according to the embodiment of the present invention.
  • Fig. 20 is a graph showing the purity analysis results of 68 Ga-NYM035 molecules according to an embodiment of the present invention by radioactive TLC scanning;
  • Fig. 21 is a PET/CT imaging result of 68 Ga-NYM035 in the 786-O, OS-RC-2 tumor-bearing mouse model according to an embodiment of the present invention, where the arrow is the tumor.
  • acetazolamide (1') is hydrolyzed under acidic conditions to obtain compound (2').
  • Compound (2') undergoes amide condensation reaction with aliphatic carboxylic acid (3') to generate compound (4').
  • the R3 functional group in the compound (4') structure and the R4 functional group in the compound (5) structure undergo amide condensation or [3+2] cycloaddition reactions, etc., to generate compound (6'), wherein R3 is Terminal group acetylene or carboxyl, R4 is azide or amino.
  • Compound (6') removes the Boc protecting group under suitable strongly acidic conditions to obtain compound (7').
  • the compound (7') undergoes a condensation reaction with the carboxyl group on the chelating group or the fluorescent group or its active ester to obtain the target compound (II).
  • Resin preparation 20.0mL of DCM solution containing Fmoc-Asp-OAll (1.00mmol, 1.00eq) and DIEA (4.00mmol, 4.00eq) was added to 2-CTC resin (1.00mmol, 1.00eq), at 20°C Nitrogen was purged, the reaction was stirred for 2 hours, MeOH (1.00 mL) was added and stirring was continued for 30.0 min. The resin was then washed with DMF (20.0 mL*5) five times, each using 20.0 mL of DMF.
  • the synthesized NYM005 precursor is chelated with radionuclide gallium [ 68 Ga] to further obtain the 68 Ga-NYM005 tracer which can be used for clinical PET/CT tracing.
  • the labeling technology is mature, and the chemical purity of the radioactive compound usually can be obtained up to 99%.
  • the labeling process is as follows, the entire labeling process can be completed within 20 minutes, and the yield of radioactive compounds can reach 70%.
  • 68 Ga nuclide was obtained by leaching the germanium gallium generator with 0.05M hydrochloric acid solution, and 1 mL of the 68 Ga nuclide (20mCi) solution was added to the reaction flask, and then Then add 1 mL of 0.3 mol/L acetic acid/sodium acetate buffer solution into the reaction flask, so that the ratio of the volume of 68 Ga nuclide to the volume of the buffer solution is 1:1, and the pH value is adjusted to 4.0.
  • the Rf value of the product is between 0.3-0.6.
  • the purity analysis results of 68 Ga-NYM005 molecular radioactive thin-layer chromatographic scanning showed that the chemical purity of the radioactive compound was 100%.
  • the experimental animal 786-O model is provided by Hengjia Biotechnology (Suzhou) Co., Ltd. It is a subcutaneous heterotopic xenograft model of 786-O tumor established on the basis of BALB/c nude mice.
  • the model is a small human renal clear cell adenocarcinoma cell. mouse model.
  • Randomly select 2 animal models give each animal 100 ⁇ Ci of the above-mentioned 68 Ga-NYM005 drug, pre-anesthetize with an appropriate concentration of isoflurane/oxygen mixed gas before scanning, and place the animals in Siemens Inveon small animal PET/CT scanning
  • the patient was continuously anesthetized with isoflurane/oxygen mixed gas on the bed, and a 10-min PET scan was performed 1 hour after administration.
  • the scanned image was obtained after the data was automatically reconstructed by the equipment software, and the scanned image was analyzed by PMOD software.
  • the 68 Ga-NYM005 drug is highly enriched in the tumor, indicating that the drug has good tumor targeting, and the drug that is not taken up by the tumor Rapidly excreted from the body through the kidney-bladder.
  • the experimental animal OS-RC-2 model is provided by Hengjia Biotechnology (Suzhou) Co., Ltd. It is a subcutaneous heterotopic xenograft model of OS-RC-2 tumor established on the basis of BALB/c nude mice. The model is constructed for human kidney cancer cells mouse model. Two animal models were selected, and each animal was given 100 ⁇ Ci of the above-mentioned 68 Ga-NYM005 drug.
  • Example 7 PET/CT scanning tissue distribution and targeting experiment of 68 Ga-NYM005 drug in 786-O tumor-bearing mouse model
  • the experimental animal 786-O model is provided by Shanghai Jiaodu Biotechnology Co., Ltd. It is based on the subcutaneous heterotopic xenograft model of 786-O tumor established in NOD-SCID mice.
  • the model is a mouse constructed from human renal clear cell adenocarcinoma Model. Two animal models were selected, and each animal was given 100 ⁇ Ci of the above-mentioned 68 Ga-NYM005 drug.
  • the experimental animal 786-O model is provided by Shanghai Jiaodu Biotechnology Co., Ltd. It is based on the subcutaneous heterotopic xenograft model of 786-O tumor established in NOD-SCID mice.
  • the model is a mouse constructed from human renal clear cell adenocarcinoma Model.
  • the scanning images were obtained after reconstruction by equipment software, and the scanning images were analyzed by PMOD software.
  • the results are shown in Figure 8 (the arrow is the tumor), adding cold medicine can significantly block the uptake of 68 Ga-NYM005 by the tumor, thus confirming that the uptake of 68 Ga-NYM005 by the tumor is a specific targeted uptake.
  • Example 9 ICR mouse tissue distribution experiment and mouse blood pharmacokinetic experiment
  • Example 10 68 Ga-NYM005 in HT29, PC3, U87 model PET scanning tissue distribution and targeting experiment
  • mice were human colon cancer cells and human prostate cancer cells, respectively.
  • Mouse models of cancer cells and human glioma One of each of the above animal models was randomly selected, and each animal was given 80 ⁇ Ci of the above-mentioned 68 Ga-NYM005 drug.
  • the experimental animal HCT116 model is provided by Hengjia Biotechnology (Suzhou) Co., Ltd. It is a subcutaneous heterotopic xenograft model of HCT116 tumor established based on BALB/c nude mice. This model is a mouse model of human colon cancer cells. Two animal models were selected, and each animal was given 100 ⁇ Ci of the above-mentioned 68 Ga-NYM005 drug.
  • mice Three ICR mice were taken, and each mouse was given 100 ⁇ Ci radiopharmaceutical 68 Ga-NYM005 for dynamic 30min scanning, and then 10min static scanning at 1h, 2h, 3h, 4h time points, according to the scanning data, different time periods in normal mice can be obtained.
  • the residence time of each organ in the mouse is calculated according to the PMOD software, and then the residence time of the organs in the mouse is calculated from the residence time of the organs in the mouse, and then the residence time of the human body is calculated by the OLINDA software
  • the total radiation effective dose is 1.221mSv/person, which is far lower than the 10-15mSv of conventional CT chest and abdomen scans
  • the dose is within the safe range
  • the radiation dose estimation table is shown in Table 3 below.
  • the patient s 18F-FDG PEC/CT imaging, a commonly used early tumor screening tracer, revealed space-occupying right kidney, bilateral lung and mediastinal lymph node metastasis, biopsy of the posterior right kidney, pathological findings: clear cell carcinoma, WHO/ISUP nuclear grading Grade 2, Vimentin9+, PAX-8+, P504S+, Ki67 10%.
  • 5mCi of 68 Ga-NYM005 sterile injection was given through the dorsal vein of the hand, and then PET/CT scan was performed for 1 hour. The imaging results are shown in Figure 13.
  • the 68 Ga-NYM005 high expression lesion in the right kidney can be consistent with the appearance of renal clear cell carcinoma, accompanied by multiple lymph node metastasis in left retroperitoneum, left hilum, aortopulmonary window, left supraclavicular, multiple metastasis in lung, left Lateral femoral head metastasis, tumor thrombus formation in inferior vena cava and pulmonary artery.
  • the 68 Ga-NYM005 molecule can detect more tumor metastases in the clinical application of kidney cancer diagnosis than the currently commonly used 18F-FDG tracer, and has more clinical application value.
  • Resin preparation add 10.0mL of DCM solution containing Fmoc-Asp-Alloc (500 ⁇ mol, 1.00eq) and DIEA (2.00mmol, 4.00eq) to 2-CTC resin (500 ⁇ mol, 1.00eq), nitrogen purging at 20°C , the reaction was stirred for 2 hours, then MeOH (500 ⁇ L) was added and stirred for 30.0 min, and then the resin was washed with DMF (20.0 mL*5) for five times, each time using 20.0 mL of DMF.
  • Feed amino acid Coupling reagent Compound 3b (1.50eq) CuI(0.50eq), DIEA(2.00eq) N-Fmoc-1,4-diaminobutane HCL(3.00eq) HOAt(3.00eq), DIC(3.00eq) DOTA-(COOt-Bu) 3 (1.50eq) HOAt(1.50eq), DIC(1.50eq)
  • the obtained crude peptide was dried under vacuum for 2 hours to obtain 400 mg of crude product.
  • the synthesized NYM034 precursor is chelated with the radionuclide gallium [ 68 Ga] to further obtain the 68 Ga-NYM034 tracer which can be used for clinical PET/CT tracing.
  • the labeling technology is mature, and the chemical purity of the radioactive compound usually can be obtained up to 99%.
  • the labeling process is as follows, the entire labeling process can be completed within 20 minutes, and the yield of radioactive compounds can reach 70%.
  • the 68 Ga nuclide was obtained by washing the germanium gallium generator with 0.05M hydrochloric acid solution. Take 1mL of the 68 Ga nuclide (20mCi) solution and add it to the reaction flask, and then add 1mL of 0.3mol/L acetic acid/sodium acetate buffer solution to the In the reaction flask, the ratio of the volume of 68 Ga nuclide to the volume of the buffer solution was 1:1, and the pH value was adjusted to 4.0.
  • the Rf value of the product is between 0.3-0.6.
  • the purity analysis results of 68 Ga-NYM034 molecular radioactive thin-layer chromatographic scanning showed that the chemical purity of the radioactive compound was 100%.
  • Example 17 68 Ga-NYM034 786-O, OS-RC-2 model PET scanning tissue distribution and targeting experiment
  • the experimental animal 786-O model is provided by Hengjia Biotechnology (Suzhou) Co., Ltd. It is a subcutaneous heterotopic xenograft model of 786-O tumor established on the basis of BALB/c nude mice.
  • the model is a small human renal clear cell adenocarcinoma cell. mouse model.
  • the experimental animal OS-RC-2 model is provided by Hengjia Biotechnology (Suzhou) Co., Ltd. It is a subcutaneous heterotopic xenograft model of OS-RC-2 tumor established on the basis of BALB/c nude mice.
  • the model is constructed for human kidney cancer cells mouse model.
  • Polypeptide synthesis The synthesis of peptides adopts the Fmoc synthesis method
  • Resin preparation Fmoc-Asp-Alloc (500 ⁇ mol, 1.00eq), DIEA (2.00mmol, 4.00eq) were dissolved in 10.0mL DCM solvent, this solution was added to 2-CTC resin, under 20 °C N 2 purging, reaction Stir for 2 hours. Then MeOH (500 ⁇ L) was added to continue stirring for 30.0 min, and then the resin was washed with DMF (20.0 mL*5) five times, each time using 20.0 mL of DMF.
  • the obtained crude peptide was dried under vacuum for 2 hours to obtain 400 mg of crude product.
  • the synthesized NYM035 precursor is chelated with radionuclide gallium [ 68 Ga] to further obtain the 68 Ga-NYM035 tracer that can be used for clinical PET/CT tracing.
  • the labeling technology is mature, and the chemical purity of the radioactive compound usually can be obtained up to 99%.
  • the labeling process is as follows, the entire labeling process can be completed within 20 minutes, and the yield of radioactive compounds can reach 70%.
  • the method for labeling NYM035 with 68 Ga in this embodiment the specific steps are as follows:
  • the 68 Ga nuclide was obtained by rinsing the germanium gallium generator with 0.05M hydrochloric acid solution, and 1 mL of the 68 Ga nuclide (20mCi) solution was added to the reaction flask, and then Then add 1 mL of 0.3 mol/L acetic acid/sodium acetate buffer solution into the reaction flask, so that the ratio of the volume of 68 Ga nuclide to the volume of the buffer solution is 1:1, and the pH value is adjusted to 4.0.
  • the Rf value of the product is between 0.3-0.6.
  • the purity analysis results of 68 Ga-NYM035 molecular radioactive thin-layer chromatographic scanning showed that the chemical purity of the radioactive compound was 100%.
  • Example 20 68 Ga-NYM035 786-O, OS-RC-2 model PET scanning tissue distribution and targeting experiment
  • the experimental animal 786-O model is provided by Hengjia Biotechnology (Suzhou) Co., Ltd. It is a subcutaneous heterotopic xenograft model of 786-O tumor established on the basis of BALB/c nude mice.
  • the model is a small human renal clear cell adenocarcinoma cell. mouse model.
  • the experimental animal OS-RC-2 model is provided by Hengjia Biotechnology (Suzhou) Co., Ltd. It is a subcutaneous heterotopic xenograft model of OS-RC-2 tumor established on the basis of BALB/c nude mice.
  • the model is constructed for human kidney cancer cells mouse model.
  • Human renal clear cell adenocarcinoma cells were selected to construct a mouse model, and a heterotopic xenograft tumor model was established. Randomly select the animal model, administer a certain amount of the molecular drug compounds (6)-(11) and compounds (15)-(18) with fluorescent groups of the present application, and perform in vivo fluorescence between 30min-120h after administration. Scanning imaging, using an appropriate concentration of isoflurane/air mixed gas for pre-anesthesia and maintenance of anesthesia during scanning, molecular drugs with fluorescent groups have high fluorescence concentration in the tumor tissue of tumor model mice, and fluorescence in other tissues Concentration is lower.
  • the above-mentioned mouse model was selected and administered, and about 24 hours later, routine organ dissection was performed under fluorescence observation.
  • the biodistribution of the drug in tumor model mice showed that it was mainly excreted out of the body through the kidneys, with high fluorescence concentration in tumor tissue and low fluorescence concentration in other tissues.

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Abstract

碳酸酐酶IX靶向放射性诊疗药物及其制备方法，具体涉及一种化合物或其药学上可接受的盐、酯或溶剂化物，其结构如式（I）所示，所述化合物能用于诊断和/或治疗一种或多种表达碳酸酐酶IX的肿瘤、癌症或细胞。

Description

碳酸酐酶IX靶向放射性诊疗药物及其制备方法
优先权信息
本申请请求2022年02月15日向中国国家知识产权局提交的、专利申请号为202210151238.9的专利申请的优先权和权益，并且通过参照将其全文并入此处。
技术领域
本发明涉及医药领域，具体地，本发明涉及碳酸酐酶(CA)IX靶向放射性诊疗药物及其制备方法，更具体地，本发明涉及式(I)或式(II)化合物或其药学上可接受的盐、酯或溶剂化物、络合物、药物组合物以及其用途。
背景技术
肾细胞癌(RCC)是最常见的肾脏赘生物。在RCC的病例中，透明细胞亚型(ccRCC)是最普遍的，占RCC的多达70％。ccRCC常见的是失去Von Hippel-Lindau(VHL)肿瘤阻抑基因。失去VHL继而导致碳酸酐酶IX(CAIX)的过表达(Bragmaier等人，2004，CAIX是一种负责催化二氧化碳可逆水合成碳酸氢根阴离子和质子的膜相关酶。CAIX的过表达已经在约95％的ccRCC肿瘤样本中被证实，使其成为用于此疾病的有用的生物标志物。
CAIX在除胃肠道、胆囊和胰管之外的正常组织和器官中具有有限的表达。没有报告证实在正常肾实质或良性肾肿块(renal mass)中的CAIX表达。基于CAIX表达的ccRCC的非侵入性诊断的可行性已经用放射性标记的抗体G250证明。然而，作为分子成像剂的抗体受到药代动力学限制，包括缓慢的血液和非靶组织清除(通常为2天-5天或更长)和非特异性器官摄取。低分子量(LMW)剂证实在施用之后的临床便利时间(clinically convenient time)内更快的药代动力学和更高的特异性信号。它们还提供了通常通过更广泛范围的化学方法和放射性核素进行的位点特异性放射性标记，并且可以提供较短的监管机构批准路径。
因而，需要越来越多的以CAIX作为靶点的靶向放射性诊疗药物正在被研发和应用。
发明内容
在本发明的第一方面，本发明提出了一种化合物或其药学上可接受的盐、酯或溶剂化 物，其结构如式(I)所示，
Figure PCTCN2022125512-appb-000001
其中，X为任选取代的5-6元环烷基、杂环基、二唑基、三唑基或酰胺基；
Y为
Figure PCTCN2022125512-appb-000002
任选取代的
Figure PCTCN2022125512-appb-000003
-COOH、
Figure PCTCN2022125512-appb-000004
任选取代的
Figure PCTCN2022125512-appb-000005
-OH、-CH(CH 3)OH、水溶性氨基酸、螯合基团或荧光基团；
Z为H、螯合基团或荧光基团；
Y、Z至少有一个为螯合基团或荧光基团；
L 1、L 2、L 3分别选自聚乙二醇链、亲水性氨基酸链、碳链或-(CH 2)nCONH-；
R 1选自被磺酸氨基取代的5-12元杂芳基；
n为1～6之间的整数。
本发明提出了一种化合物或其药学上可接受的盐、酯或溶剂化物，其结构如式(I)所示，
Figure PCTCN2022125512-appb-000006
其中，X选自5-6元杂环基、二唑基、三唑基和酰胺基；
Y选自
Figure PCTCN2022125512-appb-000007
-OH、-CH(CH 3)OH、水溶性氨基酸、螯合基团和荧光基团；
Z选自H、螯合基团和荧光基团；
L 1、L 2、L 3分别选自聚乙二醇链、亲水性氨基酸链和碳链；
R 1选自被磺酸氨基取得的5-12元杂芳基。
本发明的一些方案中，上述聚乙二醇链为由一个或多个聚乙二醇单元(-O-(CH 2) 2-O-)形成的链，如由1、2、3、4、5、6、7或8个聚乙二醇单元(-O-(CH 2) 2-O-)形成的链，其余变量如本发明所定义。
本发明的一些方案中，上述亲水性氨基酸链为由一个或多个相同或不同的亲水性氨基 酸缩合形成的链，如由1、2、3、4、5、6、7或8个亲水性氨基酸缩合形成的链，所述亲水性氨基酸为侧链具有高亲水性的氨基酸之总称，如亲水性的氨基酸包括选自苏氨酸(Thr)、丝氨酸(Ser)、半胱氨酸(Cys)、天冬酰胺(Asn)、谷氨酰胺(Gln)、酪氨酸(Tyr)、赖氨酸(Lys)、精氨酸(Arg)、组氨酸(His)、天冬氨酸(Asp)或谷氨酸(Glu)，其余变量如本发明所定义。
本发明的一些方案中，上述碳链是指由一个或多个取代或未被取代的直链烷基或支链烷基形成的碳链，如由1、2、3、4、5、6、7或8个碳原子组成的取代或未被取代的直链烷基或支链烷基形成的碳链，其余变量如本发明所定义。
本发明的一些方案中，上述R 1选自
Figure PCTCN2022125512-appb-000008
如
Figure PCTCN2022125512-appb-000009
其余变量如本发明所定义。
在本发明的另一方面，本发明还提出了一种化合物或其药学上可接受的盐、酯或溶剂化物，其特征在于，其结构如式(II)所示，
Figure PCTCN2022125512-appb-000010
其中，X为5-6元杂环基、环烷基、二唑基、三唑基或酰胺基；
Y’为
Figure PCTCN2022125512-appb-000011
任选取代的
Figure PCTCN2022125512-appb-000012
-COOH、
Figure PCTCN2022125512-appb-000013
任选取代的
Figure PCTCN2022125512-appb-000014
-OH、-CH(CH 3)OH、水溶性氨基酸、螯合基团或荧光基团；
Z为H、螯合基团或荧光基团；
Y’、Z至少有一个为螯合基团或荧光基团。
在本发明的另一方面，本发明还提出了一种化合物或其药学上可接受的盐、酯或溶剂化物，其特征在于，其结构如式(II)所示，
Figure PCTCN2022125512-appb-000015
其中，X选自任选取代的5-6元杂环基、二唑基、三唑基和酰胺基；
Y选自
Figure PCTCN2022125512-appb-000016
-OH、-CH(CH 3)OH、水溶性氨基酸、螯合基团和荧光基团；
Z选自H、螯合基团或荧光基团。
在本发明的一些方案中，上述X选自
Figure PCTCN2022125512-appb-000017
Figure PCTCN2022125512-appb-000018
其余变量如本发明所定义。
在本发明的一些方案中，上述X选自
Figure PCTCN2022125512-appb-000019
其余变量如本发明所定义。
在本发明的一些方案中，上述螯合基团选自1,4,7,10-四氮杂环十二烷-N,N`,N``,N```,-四乙酸、1,4,7-三氮杂环壬烷-1,4,7-三乙酸、2-(4,7-双(羧甲基)-1,4,7-三偶氮壬-1-基)戊二酸、2-(4,7,10-三(羧甲基)-1,4,7,10-四氮杂环十二烷-1-基)戊二酸、1,4,7-三氮杂环壬烷次膦酸、1,4,7-三氮杂环壬烷-1-[甲基(2-羧乙基)次膦酸]-4,7-双[甲基(2-羧甲基)次膦酸]、N’-{5-[乙酰基(羟基)氨基]戊基}-N-[5-({4-[5-氨基戊基)(羟基)氨基]-4-氧丁酰基}氨基)戊基]-N-羟基琥珀酰胺、二乙三胺五乙酸、反式-环己基-二乙三胺五乙酸、对异氰硫基苄基-二乙三胺五乙酸、1-(异氰硫基苄基)-3-甲基-二乙三胺五乙酸、1-(异氰硫基苄基)-4-甲基-二乙三胺五乙酸、1-(2)-甲基-4-异氰基苄基-二乙三胺五乙酸、1-氧杂-4,7,10-三氮杂环十二烷-4,7,10-三乙酸、6-肼基烟酸琥珀酰亚胺酯盐酸盐和巯基乙酰基三甘氨酸，其余变量如本发明所定义。
在本发明的一些方案中，上述荧光基团选自花青素类荧光染料，其中包括非磺化花青 染料和磺化花青染料，其余变量如本发明所定义。
在本发明的一些方案中，所述花青素类荧光染料选自Cy3、Cy3.5、Cy5、Cy5.5、Cy7、Cy7.5、磺化-Cy3，磺化-Cy5或磺化-Cy7或ICG等，其余变量如本发明所定义。
在本发明的一些方案中，上述荧光基团选自
Figure PCTCN2022125512-appb-000020
Figure PCTCN2022125512-appb-000021
在本发明的再一方面，本发明还提出了一种化合物或其药学上可接受的盐、酯或溶剂化物，其结构选自如下一种：
Figure PCTCN2022125512-appb-000022
Figure PCTCN2022125512-appb-000023
Figure PCTCN2022125512-appb-000024
Figure PCTCN2022125512-appb-000025
在本发明的再一方面，本发明还提出了一种化合物。根据本发明的实施例，所述化合物由前面所述的化合物或其药学上可接受的盐、酯或溶剂化物与放射性核素或非放射性元素共价而成。
在本发明的一些方案中，所述放射性核素选自 68Ga、 18F、 99mTc、 89Zr、 111In、 45Ti、 59Fe、 64Cu、 94mTc、 67Ga、 71/72/74As、 43/44Sc、 82mRb、 52Mn、 86Y、 125I、 124I、 76Br、 177Lu、 90Y、 131I、 153Sm、 67Cu、 89Sr、 137Cs、 166Ho、 177Yb、 105Rh、 186/188Re、 47Sc、 212/213Bi、 225Ac、 212Pb、 149Pm、 211At、 223Ra和 227Th。
在本发明的一些方案中，所述放射性核素选自 131I。根据本发明的实施例，其标记位点为酪氨酸酚羟基上，且可以与其他核素(如 68Ga)同时标记，同时在一个分子上同时实现诊断和治疗功能。
在本发明的一些方案中，所述非放射性元素选自Ga、Fe和Gd。
在本发明的一些方案中，所述放射性核素选自 18F。
在本发明的一些方案中，所述放射性核素 18F络合是通过放射性同位素氟化铝形成的。
在本发明的再一方面，本发明还提出了一种化合物，根据本发明的实施例，所述化合物的结构选自如下之一：
Figure PCTCN2022125512-appb-000026
Figure PCTCN2022125512-appb-000027
Figure PCTCN2022125512-appb-000028
Figure PCTCN2022125512-appb-000029
Figure PCTCN2022125512-appb-000030
在本发明的再一方面，本发明还提出了一种药物组合物。根据本发明的实施例，所述药物组合物包含前面所述的化合物、或其药学上可接受的盐、酯或溶剂化物，和药学上可接受的载体、辅料等。
在本发明的再一方面，本发明还提出了前面所述的化合物，或其药学上可接受的盐、酯或溶剂化物，或前面所述的药物组合物在制备用于诊断和/或治疗一种或多种表达碳酸酐酶IX的肿瘤、癌症或细胞的试剂和/或药物中的用途。
在本发明的一些方案中，上述诊断的形式选自光学成像和/或核素成像。
在本发明的一些方案中，上述诊断的形式选自荧光显像、PET成像和/或SPECT成像。
在本发明的一些方案中，上述治疗选自放射性治疗和/或辅助手术开展荧光手术导航。
在本发明的一些方案中，上述肿瘤、癌症选自肾癌、脑胶质瘤及其他实体瘤和/或其转移病灶。
在本发明的再一方面，本发明还提出了前面所述的化合物或其药学上可接受的盐、酯或溶剂化物或前面所述的药物组合物，用于诊断和/或治疗表达碳酸酐酶IX的肿瘤、癌症或细胞。
在本发明的再一方面，本发明还提出了所述的化合物或其药学上可接受的盐、酯或溶剂化物或前面所述的药物组合物，用于诊断和/或治疗肾癌、脑胶质瘤及其他实体瘤和/或其转移病灶。
在本发明的再一方面，本发明还提出了一种诊断和/或治疗表达碳酸酐酶IX的肿瘤、癌症或细胞的方法。根据本发明的实施例，给予患者药学上可接受剂量的前面所述的化合物或其药学上可接受的盐、酯或溶剂化物或前面所述的药物组合物。
根据本发明的实施例，所述所述表达碳酸酐酶IX的相关疾病为肾癌、脑胶质瘤及其他实体瘤和/或其转移病灶。
在本发明的再一方面，本发明还提出了一种试剂盒。根据本发明的实施例，所述试剂盒包含前面所述的化合物，或其药学上可接受的盐、酯或溶剂化物，或前面所述的药物组合物。
在本发明的一些方案中，所述试剂盒进一步包含药学上可接受的载体、辅料，其余变量如本发明所定义。
在本发明的一些方案中，前面所述药学上可接受的载体、辅料包括灭菌注射用水、醋酸/醋酸钠缓冲溶液和抗坏血酸钠。
在本发明的一些方案中，所述试剂盒是通过如下方法制备获得的：
1)以灭菌注射用水为溶剂配制0.15-10mg/mL的前面所述的化合物的前体溶液，并按5-50μg/瓶进行分装；
2)以灭菌注射用水为溶剂配制0.2-0.5mol/L的醋酸/醋酸钠缓冲溶液(pH 3.5-4.5)，并按0.2-2mL/瓶进行分装；
3)以灭菌注射用水为溶剂配制20-80mg/mL的抗坏血酸钠溶液，按0.1-1mL/瓶进行分装。
在本发明的一些方案中，上述所有溶液皆在整体C级且局部为A级的超净台下进行。
在本发明的再一方面，本发明还提出了前面所述试剂盒用于诊断和/或治疗一种或多种表达碳酸酐酶IX的肿瘤、癌症。根据本发明的实施例，所述诊断的形式选自光学成像和/或核素成像。
在本发明的一些方案中，上述诊断的形式选自荧光显像、PET成像和/或SPECT成像。
在本发明的一些方案中，上述治疗选自放射性治疗和/或辅助手术开展荧光手术导航。
在本发明的一些方案中，上述肿瘤、癌症选自肾癌、脑胶质瘤及其他实体瘤和/或其转移病灶。
根据本发明的实施例，本发明相对于现有技术至少具有如下优势效果至少之一：
1、本发明化合物的合成原料更易获得，合成工艺更简单，收率高。
2、本发明的化合物采用了水溶性氨基酸，分子结构简单，分子量小，利于该分子在正常组织脏器的清除，大大临床应用时患者内照射剂量，同时工艺更为简单。
3、本发明化合物的分子结构主干中，主要使用了酰胺键和氨基酸，使得该分子可以使用多肽固相合成技术进行合成，同时分子量较小合成步骤少，大大较低了分子在IND新药申报过程中的化学成分生产和控制(CMC)难度，且进一步降低了杂质研究难度。
4.本发明通过分子结构优化，将分子量较大的放射性核素螯合基团与碳酸酐酶IX靶点靶向基团结合到一起，在一个分子上实现多种功能，且根据目前非临床和临床实验结果，分子在放射性诊断示踪(PET/CT或SPECT/CT扫描)方面效果好，且分子安全性好。
5、本发明化合物结构进一步拓展了适合的荧光基团，通过荧光基团可以实现荧光显像，并可进一步协助医生进行荧光手术导航(荧光基团随该分子靶向到肿瘤后，肿瘤会带荧光， 正常组织则没有荧光，医生在手术过程中能很容易的区分健康组织和肿瘤组织，进行大大提高手术效果)。
定义和一般术语
本发明将会把确定的具体化的内容所对应的文献详细列出，实施例都伴随有结构式和化学式的图解。本发明有预期地涵盖所有的选择余地、变体和同等物，这些可能如权利要求所定义的那样包含在本发明范围内。所属领域的技术人员将识别许多类似或等同于在此所描述的方法和物质，这些可以应用于本发明的实践中去。本发明绝非限于方法和物质的描述。有很多文献和相似的物质与本发明申请相区别或抵触，其中包括但绝不限于术语的定义，术语的用法，描述的技术，或如本发明申请所控制的范围。
本发明将应用以下定义除非其他方面表明。根据本发明的目的，化学元素根据元素周期表，CAS版本和化学物理手册，75 th Ed.，1994来定义。另外，有机化学一般原理见“Organic Chemistry”,Thomas Sorrell,University Science Books,Sausalito,1999,和“March's Advanced Organic Chemistry”,Michael B.Smith和Jerry March,John Wiley&Sons,New York,2007，所有上述参考文献均通过引用并入本文中。
如本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者如实施例里面特殊的例子，子类，和本发明所包含的一类化合物。应了解“任选取代的”这个术语与“取代或未取代的”这个术语可以交换使用。一般而言，术语“任选地”不论是否位于术语“取代的”之前，表示所给结构中的一个或多个氢原子可以被具体取代基所取代，也可以不被取代。除非其他方面表明，一个任选的取代基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。其中所述的取代基可以是，但并不限于，氘、羟基、氨基、卤素、氰基、芳基、杂芳基、烷氧基、烷氨基、烷硫基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、杂芳氧基、氧代(＝O)、羧基、羟基取代的烷氧基、羟基取代的烷基-C(＝O)-、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O) 2-、羟基取代的烷基-S(＝O)-、羟基取代的烷基-S(＝O) 2-、羧基取代的烷氧基等等。
除非另有说明，术语“烷基”，表示1-20个碳原子，或1-10个碳原子，或1-8个碳原子，或1-6个碳原子，或1-4个碳原子，或1-3个碳原子的饱和直链或支链的单价烃基，其中烷基可以独立且任选地被一个或多个本发明所描述的取代基所取代，取代基包括但不限于，氘、氨基、羟基、氰基、F、Cl、Br、I、巯基、硝基、氧代(＝O)等等。烷基的实例包括，但并不限于，甲基(Me，-CH 3)、乙基(Et，-CH 2CH 3)、正丙基(n-Pr，-CH 2CH 2CH 3)、异丙 基(i-Pr，-CH(CH 3) 2)、正丁基(n-Bu，-CH 2CH 2CH 2CH 3)、异丁基(i-Bu，-CH 2CH(CH 3) 2)、仲丁基(s-Bu，-CH(CH 3)CH 2CH 3)、叔丁基(t-Bu，-C(CH 3) 3)、正戊基(-CH 2CH 2CH 2CH 2CH 3)、2-戊基(-CH(CH 3)CH 2CH 2CH 3)、3-戊基(-CH(CH 2CH 3) 2)、2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)、3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)、3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)、2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)、正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)、2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)、3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))、2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)、3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)、4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)、3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)、2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)、2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)、3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)、正庚基、正辛基等等。术语“烷基”和其前缀“烷”在此处使用，都包含直链和支链的饱和碳链。术语“烷撑”在此处使用，表示从直链或支链饱和碳氢化物消去两个氢原子得到的饱和二价烃基，这样的实例包括，但并不限于，亚甲基、次乙基、次异丙基等等。
术语“环烷基”是指有一个或多个连接点连接到分子的其余部分，饱和的，含有3-12个环碳原子的单环，双环或三环体系。其中一些实施例，环烷基是含3-10个环碳原子的环体系；另外一些实施例，环烷基是含3-8个环碳原子的环体系；另外一些实施例，环烷基是含3-6个环碳原子的环体系；另外一些实施例，环烷基是含5-6个环碳原子的环体系；且所述环烷基基团可以独立地未被取代或被一个或多个本发明所描述的取代基所取代。
术语“芳基”可以单独使用或作为“芳烷基”、“芳烷氧基”或“芳氧基烷基”的一大部分，表示共含有6-14元环的单环、双环和三环的碳环体系，其中，至少一个环体系是芳香族的，其中每一个环体系包含3-7元环，且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”交换使用，如芳香环可以包括苯基，萘基和蒽基。并且所述芳基可以是取代或未取代的，其中取代基可以是，但并不限于，氘、羟基、氨基、卤素、氰基、芳基、杂芳基、烷氧基、烷氨基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、羟基取代的烷氧基、羟基取代的烷基-C(＝O)-、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O) 2-、羟基取代的烷基-S(＝O)-、羟基取代的烷基-S(＝O) 2-、羧基取代的烷氧基等等。
术语“杂芳基”可以单独使用或作为“杂芳基烷基”或“杂芳基烷氧基”的一大部分，表示共含有5-14元环的单环、双环和三环体系，其中至少一个环体系是芳香族的，且至少一个环体系包含一个或多个杂原子，其中杂原子具有本发明所述的含义，其中每一个环体系包含3-7元环，且有一个或多个附着点与分子其余部分相连。术语“杂芳基”可以与术语“芳杂环”或“杂芳族化合物”交换使用。并且所述杂芳基可以是取代或未取代的，其中取代基可以是， 但并不限于，氘、羟基、氨基、卤素、氰基、芳基、杂芳基、烷氧基、烷氨基、烷基、烯基、炔基、杂环基、巯基、硝基、芳氧基、羟基取代的烷氧基、羟基取代的烷基-C(＝O)-、烷基-C(＝O)-、烷基-S(＝O)-、烷基-S(＝O) 2-、羟基取代的烷基-S(＝O)-、羟基取代的烷基-S(＝O) 2-、羧基取代的烷氧基等等。
另外一些实施方案是，芳杂环包括以下的单环，但并不限于这些单环：2-呋喃基、3-呋喃基、N-咪唑基、2-咪唑基、4-咪唑基、5-咪唑基、3-异噁唑基、4-异噁唑基、5-异噁唑基、2-噁唑基、4-噁唑基、5-噁唑基、4-甲基异噁唑-5-基、N-吡咯基、2-吡咯基、3-吡咯基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、嘧啶-5-基、哒嗪基(如3-哒嗪基)、2-噻唑基、4-噻唑基、5-噻唑基、四唑基(如5-四唑基)、三唑基(如2-三唑基和5-三唑基)、2-噻吩基、3-噻吩基、吡唑基(如2-吡唑基)、异噻唑基、1,2,3-噁二唑基、1,2,5-噁二唑基、1,2,4-噁二唑基、1,2,3-三唑基、1,2,3-硫代二唑基、1,3,4-硫代二唑基、1,2,5-硫代二唑基、1,3,4-噻二唑-2-基、吡嗪基、吡嗪-2-基、1,3,5-三嗪基、苯并[d]噻唑-2-基、咪唑并[1,5-a]吡啶-6-基；也包括以下的双环，但绝不限于这些双环：苯并咪唑基、苯并呋喃基、苯并噻吩基、吲哚基(如2-吲哚基)、嘌呤基、喹啉基(如2-喹啉基、3-喹啉基、4-喹啉基)和异喹啉基(如1-异喹啉基、3-异喹啉基或4-异喹啉基)。
术语“卤素”表示F，Cl，Br和I。
另外，需要说明的是，除非以其他方式明确指出，在本文中通篇采用的描述方式“各…独立地为”和“…和…各自独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相不影响，例如结构
Figure PCTCN2022125512-appb-000031
和结构
Figure PCTCN2022125512-appb-000032
两者中的R 6具体选项互相之间不受影响，同时，在同一结构中出现多个R 6的，多个R 6之间具体选项互不影响，即R 6的具体选项可以相同，也可以不同。
本发明中立体化学的定义和惯例的使用通常参考以下文献：S.P.Parker,Ed.,McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York；and Eliel,E.and Wilen,S.,"Stereochemistry of Organic Compounds",John Wiley&Sons,Inc.,New York,1994。本发明的化合物可以包含不对称中心或手性中心，因此存在不同的立体异构体。本发明的化合物所有的立体异构形式，包括但绝不限于，非对映体、对映异构体、阻转异构体和它们的混合物，如外消旋混合物，组成了本发明的一部分。很多有机化合物都以光学活性形式存在，即它们有能力旋转平面偏振光的平面。在描述光学活性化合物时， 前缀D、L或R、S用来表示分子手性中心的绝对构型。前缀d、l或(+)、(-)用来命名化合物平面偏振光旋转的符号，(-)或l是指化合物是左旋的，前缀(+)或d是指化合物是右旋的。这些立体异构体的化学结构是相同的，但是它们的立体结构不一样。特定的立体异构体可以是对映体、异构体的混合物通常称为对映异构体混合物。50:50的对映体混合物被称为外消旋混合物或外消旋体，这可能导致化学反应过程中没有立体选择性或立体定向性。术语“外消旋混合物”和“外消旋体”是指等摩尔的两个对映异构体的混合物，缺乏光学活性。
术语“互变异构体”或“互变异构的形式”是指不同能量的结构的同分异构体可以通过低能垒互相转化。例如质子互变异构体(即质子移变的互变异构体)包括通过质子迁移的互变，如酮式-烯醇式和亚胺-烯胺的同分异构化作用。原子价(化合价)互变异构体包括重组成键电子的互变。
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,J.Pharmaceutical Sciences,66,1-19,1977所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐，如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、高氯酸盐，和有机酸盐，如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸盐、琥珀酸盐、丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等等。通过适当的碱得到的盐包括碱金属、碱土金属，铵和N +(C 1-4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠、锂、钾、钙、镁等等。药学上可接受的盐进一步包括适当的、无毒的铵/季铵盐和抗平衡离子形成的胺阳离子，如卤化物、氢氧化物、羧化物、硫酸化物、磷酸化物、硝酸化物、C 1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸、氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
如本说明书所用，术语“治疗”可以包括逆转、减轻、抑制所述疾病的发展、预防或降低所述疾病或所述术语所适用的状况或所述疾病或病症的一个或多个症状或表现。
“预防”是指不引起一疾病、病症、症状或表现或严重程度的恶化。因此，可以预防性地以当前公开的所述多个化合物进行给药，以预防或减少所述疾病或病症的发生或复发。
如本发明所使用的术语“治疗”任何疾病或病症，是指所有可以减缓、中断、阻止、控制或停止疾病或病症的进展，但不一定表示所有疾病或病症的症状全部消失，其也包括对所述症状的预防性治疗，尤其是在容易患有这样疾病或障碍的患者中。在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
如本发明所使用的术语“治疗有效量”或“治疗有效剂量”是指能够引发个体的生物学或医学响应(例如降低或抑制酶或蛋白质活性，或改善症状、缓解病症、减缓或延迟疾病发展，或预防疾病等)的本发明化合物的量。在一项非限定性的实施方案中，术语“治疗有效量”是指当向个体施用本发明化合物时，对以下情况有效的量：(1)至少部分地缓解、抑制、预防和/或改善(i)由碳酸酐酶IX介导，或者(ii)与碳酸酐酶IX活性相关，或者(iii)由碳酸酐酶IX的异常活性表征的病症或疾病；或者(2)降低或抑制碳酸酐酶IX的活性；或者(3)降低或抑制碳酸酐酶IX的表达。在另一实施方案中，术语“治疗有效量”是指当向细胞、或器官、或非细胞生物物质、或介质施用时，能至少部分地降低或抑制碳酸酐酶IX活性；或者至少部分地降低或抑制碳酸酐酶IX表达的有效的本发明化合物的量。
如本发明所使用的术语化合物“给予”和“给药”化合物应当理解为向需要其的个体提供本发明的化合物或本发明化合物的盐、酯或溶剂化物。应当认识到本领域技术人员通过使用有效量的本发明化合物治疗目前患有表达碳酸酐酶IX的疾病，例如肾癌、脑胶质瘤及其他实体瘤和/或其转移病灶。
以下缩写贯穿本发明：
DOTA代表1,4,7,10-四氮杂环十二烷-N,N`,N``,N```,-四乙酸，NOTA代表1,4,7-三氮杂环壬烷-1,4,7-三乙酸，NODAGA代表2-(4,7-双(羧甲基)-1,4,7-三偶氮壬-1-基)戊二酸，DOTAGA代表2-(4,7,10-三(羧甲基)-1,4,7,10-四氮杂环十二烷-1-基)戊二酸，TRAP代表1,4,7-三氮杂环壬烷次膦酸，NOPO代表1,4,7-三氮杂环壬烷-1-[甲基(2-羧乙基)次膦酸]-4,7-双[甲基(2-羧甲基)次膦酸]，DFO代表N’-{5-[乙酰基(羟基)氨基]戊基}-N-[5-({4-[5-氨基戊 基)(羟基)氨基]-4-氧丁酰基}氨基)戊基]-N-羟基琥珀酰胺，DTPA代表二乙三胺五乙酸，CHX-DTPA代表反式-环己基-二乙三胺五乙酸，SCN-Bz-DTPA代表对异氰硫基苄基-DTPA，1B3M代表1-(异氰硫基苄基)-3-甲基-DTPA；1B3B代表1-(异氰硫基苄基)-4-甲基-DTPA；MX-DTPA代表1-(2)-甲基-4-异氰基苄基-DTPA；氧-Do3A代表2-氧杂咱-4,7,10-三氮杂环十二烷-4,7,10-三乙酸，HYNIC代表6-肼基烟酸琥珀酰亚胺酯盐酸盐；MAG3代表巯基乙酰基三甘氨酸。
磺化-Cy7荧光基团结构如下
Figure PCTCN2022125512-appb-000033
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1是根据本发明实施例的NYM005分子的LC-MS谱图；
图2是根据本发明实施例的NYM005分子的HPLC谱图；
图3是根据本发明实施例的 68Ga-NYM005分子的放射性薄层色谱扫描纯度分析结果图；
图4是根据本发明实施例的病理切片图，其中上图为HE病理切片病灶图，下图为切片成像图；
图5是根据本发明实施例的 68Ga-NYM005药物在786-O荷瘤鼠模型上的PET/CT显像结果图，其中箭头处为肿瘤处；
图6是根据本发明实施例的 68Ga-NYM005药物在OS-RC-2荷瘤鼠模型上的PET/CT显像结果图，其中箭头处为肿瘤处；
图7是根据本发明实施例的 68Ga-NYM005药物在786-O荷瘤鼠模型上的PET/CT扫描组织分布及靶向性显像结果图，其中箭头处为肿瘤处；
图8是根据本发明实施例的 68Ga-NYM005药物在786-O荷瘤鼠模型上竞争抑制结果图，其中箭头处为肿瘤处；
图9是根据本发明实施例的小鼠的血药浓度-时间图；
图10是根据本发明实施例的 68Ga-NYM005在HT29、PC3、U87荷瘤鼠模型上的PET/CT显像结果图，其中箭头处为肿瘤处；
图11是根据本发明实施例的 68Ga-NYM005在HCT116荷瘤鼠模型上的PET/CT显像结果图，其中箭头处为肿瘤处；
图12是根据本发明实施例的小鼠的体重变化图；
图13是根据本发明实施例的 68Ga-NYM005荧光分子科研临床PET/CT显像结果；
图14是根据本发明实施例的NYM034分子LC-MS谱图；
图15是根据本发明实施例的NYM034分子的HPLC谱图；
图16是根据本发明实施例的 68Ga-NYM034分子的放射性薄层色谱扫描纯度分析结果图；
图17是根据本发明实施例的 68Ga-NYM034在786-O、OS-RC-2荷瘤鼠模型上的PET/CT显像结果图，其中箭头处为肿瘤处；
图18是根据本发明实施例的NYM035分子LC-MS谱图；
图19是根据本发明实施例的NYM035分子的HPLC谱图；
图20是根据本发明实施例的 68Ga-NYM035分子的放射性薄层色谱扫描纯度分析结果图；
图21是根据本发明实施例的 68Ga-NYM035在786-O、OS-RC-2荷瘤鼠模型上的PET/CT显像结果图，其中箭头处为肿瘤处。
具体实施方式
下面参考具体实施例，对本发明进行描述，需要说明的是，这些实施例仅仅是描述性的，而不以任何方式限制本发明。
实施例1
Figure PCTCN2022125512-appb-000034
合成路线：
Figure PCTCN2022125512-appb-000035
首先，将乙酰唑胺(1’)在酸性条件下发生水解，得到化合物(2’)。化合物(2’)与脂肪羧酸(3’)发生酰胺缩合反应，生成化合物(4’)。之后，化合物(4’)结构中的R 3官能团与化合物(5)结构中的R 4官能团发生酰胺缩合或[3+2]环加成反应等，生成化合物(6’)，其中R 3为端基乙炔或羧基，R 4为叠氮或氨基。化合物(6’)在适宜的强酸性条件下脱除Boc保护基团，得到化合物(7’)。最后，化合物(7’)与螯合基团或荧光基团上的羧基或其活性酯发生缩合反应，制得目标化合物(II)。
实施例2 NYM005分子的制备过程
Figure PCTCN2022125512-appb-000036
NYM005分子结构
其LC-MS谱图见图1，HPLC谱图见图2。
合成路线：
步骤一：
Figure PCTCN2022125512-appb-000037
化合物(1b)(5.00g,22.5mmol,1.00eq)加入到50mL的EtOH溶剂中，25℃下加入盐酸(12.0M,7.50mL,4.00eq))，将此混合物在78℃条件下回流16小时，TLC法(体积比：二氯甲烷：甲醇＝5：1)结果显示有新化合物生成，将反应溶液冷却至25℃，将反应混合物倒入水(30.0mL)中，加入饱和碳酸氢钠，调整pH至7，用乙酸乙酯(30.0mL*3)进行萃取，萃取三次，每次使用乙酸乙酯30mL。萃取后的有机层用30mL饱和食盐水洗涤，再经过无水硫酸钠干燥，减压蒸去溶剂，得到残留物。残留物为黄色油状物(2b)(12.0g，35.0mmol)。
步骤二：
Figure PCTCN2022125512-appb-000038
化合物(a)(2.00g、17.8mmol、1.94mL、1.00mL)添加到DCM(20.0mL)溶剂内，向此溶液内添加DMF(65.1mg,891μmol,68.6μL,0.05eq)，将溶液冷却至0℃，逐滴加入草酰二氯(2.15g,16.9mmol,1.48mL,0.95eq)，在20℃下搅拌3h。将反应混合物加压浓缩得到hex-5-ynoyl chloride(2.03g,15.5mmol)，为黄色油状物。
将化合物(2b)(2.70g,14.9mmol,1.00eq)和吡啶(2.37g,29.9mmol,2.42mL,2.00eq)添加到DMF溶剂内(28.0mL)形成混合物，冷却至0℃。将hex-5-ynoyl chloride(1.96g,14.9mmol,1.00eq)溶于DCM溶剂内(20.0mL)，并在0℃下逐滴加入到前混合物内，在25℃搅拌12小时。将反应后的混合物减压浓缩，去除溶剂得到残渣。用制备-高效液相色谱纯化得到白色固体化合物(3b)(2.75g,9.95mmol)。
步骤三：
多肽的合成:多肽的合成采用Fmoc合成法
Figure PCTCN2022125512-appb-000039
1.树脂制备:将含有Fmoc-Asp-OAll(1.00mmol,1.00eq)和DIEA(4.00mmol,4.00eq)的DCM溶液20.0mL加入到2-CTC树脂(1.00mmol,1.00eq)，20℃下氮气吹扫，反应搅拌2小时，加入MeOH(1.00mL)继续搅拌30.0min。随后用DMF(20.0mL*5)洗涤树脂，洗涤五次，每次使用DMF 20.0mL。
2.脱保护:将含有20％哌啶的DMF(20.0mL)溶液加入到树脂内，在氮气吹扫下搅拌30.0min，用DMF(20.0mL*5)洗涤过滤树脂，洗涤五次，每次使用DMF 20.0mL。
3.偶联:在DMF(10.0mL)溶剂内加入5-叠氮戊酸(3.00mmol,3.00eq)，并加入HATU(3.00mmol,3.00eq)和DIEA(6.00mmol,6.00eq)，将混合物加入到树脂内，在20℃下，氮气吹扫下搅拌30.0min，用DMF(20.0mL*5)洗涤树脂，洗涤五次，每次使用DMF 20.0mL。
4.在DMF(20.0mL)溶剂内加入化合物(3b)(3.00mmol,3.00eq)、CuI(0.50mmol,0.50eq)、DIEA(4.00mmol,4.00eq)，氮气吹扫20℃下搅拌16小时，然后用DMF(20.0mL*5)洗涤树脂，洗涤五次，每次使用DMF 20.0mL。
5.脱保护:在树脂中加入PhSiH 3(10.0mmol,10.0eq)和Pd(PPh 3) 4(0.10mmol,0.10eq)，氮气吹扫下搅拌15.0min*3，搅拌三次，每次15min。用DMF(20.0mL*5)洗涤过滤树脂，洗涤五次，每次使用DMF 20.0mL。
6.重复上述步骤2-3，偶联表1中氨基酸:
表1
投料氨基酸 偶联试剂
N-Fmoc-1,4-Diaminobutane .HCl(3.00eq) HOAT(3.00eq)、DIC(3.00eq)
NOTA-bis(tBu)ester(1.50eq) HOAT(1.50eq)、DIC(1.50eq)
7.用DMF(20.0mL*5)洗涤树脂，洗涤五次，每次使用DMF 20.0mL，过滤得到多肽(4b)。
8.多肽的裂解和纯化：
用MeOH(20.0mL*3)洗涤树脂，洗涤三次，每次使用MeOH 20.0mL，真空干燥，得到2.0g多肽树脂(4b)；将带有侧链保护基的多肽加入到烧瓶内，并添加20mL裂解缓冲 液(92.5％TFA/2.5％TIS/2.5％H20/2.5％MPR))，20℃下搅拌2小时进行脱保护；用叔丁基甲基醚(100mL)沉淀并离心(3.00min，3000rpm)，再用叔丁基甲基醚洗涤肽沉淀两次(100.0ml)。将得到的产物真空干燥2小时，得到0.821g粗产物。
用制备-高效液相色谱法(TFA条件:A:0.075％TFA的H20溶液，B:ACN)纯化，得到目标产物NYM005(105mg,101umol，纯度96.30％)，为白色固体。
实施例3  68Ga-NYM005的制备过程
合成的NYM005前体经与放射性核素镓[ 68Ga]螯合反应进一步获得可用于临床PET/CT示踪的 68Ga-NYM005示踪剂，其标记技术成熟，通常标记产物放射性化合物化学纯度可达到99％。
标记过程如下所示，全部标记过程可以在20min内完成，放射性化合物产率可达到70％。
Figure PCTCN2022125512-appb-000040
68Ga-NYM005标记过程
本实施例的 68Ga标记NYM005的方法，具体步骤如下： 68Ga核素经0.05M盐酸溶液淋洗锗镓发生器获得，取1mL该 68Ga核素(20mCi)溶液加入到反应瓶中，然后再加入1mL 0.3mol/L醋酸/醋酸钠缓冲溶液加入到反应瓶中，使 68Ga核素体积与缓冲溶液体积比为1：1，调节pH值为4.0。取NYM005前体化合物适量加入到灭菌注射用水中配制成1mg/mL的前体溶液，然后取45nmol(40ug)加入到反应瓶中，于105度下反应6min，反应完成后冷却1min，用10mL无菌注射器取5mL灭菌注射用水加入到反应瓶中稀释反应液并达到降低反应液温度的目的，再将反应瓶内全部液体抽到注射器内，取出预先活化的Sep-Pak C-18小柱接到注射器出口端，推动反应稀释液流经Sep-Pak C-18小柱，目标产物 68Ga-NYM005被C-18小柱吸附，然后用1mL 70％医用级无水乙醇溶液淋洗C-18小柱，淋洗液经0.22μm无菌滤膜过滤后流入无菌真空瓶内，再加入4mL生理盐水溶液，即得 68Ga-NYM005无菌注射液。
使用放射性薄层色谱法对上述产品进行质控，载体为玻璃纤维纸，展开剂为0.5M柠檬酸/柠檬酸钠缓冲液(pH＝5)。取玻璃纤维纸，用移液枪移取样品轻轻点在玻璃纤维纸距离底部1.5cm处，放入事先加入500μL 0.5M柠檬酸/柠檬酸钠缓冲液(pH＝5)试管中，展开 到距离色谱纸顶部2.5cm处取出晾干，Radio-TLC薄层扫描仪检测。在0.5M柠檬酸/柠檬酸钠缓冲液(pH＝5)体系下，产物的Rf值在0.3-0.6之间。如图3所示， 68Ga-NYM005分子放射性薄层色谱扫描纯度分析结果，放射性化合物化学纯度100％。
实施例4  68Ga-NYM005放射性自显影实验
将胰腺癌和肾透明细胞癌石蜡切片烘制与脱蜡水化，配置所需浓度的 68Ga-NYM005药物，每片切片按0.3-0.4ml体积进行放射药物 68Ga-NYM005孵育，室温下孵育35min，孵育完成后进行洗脱、烘干，然后将切片进行磷屏成像。胰腺癌切片成像结果如图4所示，显示无明显放射性浓聚，肾细胞癌切片成像结果显示有高放射性浓聚且与HE病理切片病灶位置吻合。
实施例5  68Ga-NYM005药物在786-O荷瘤鼠模型上的显像结果
实验动物786-O模型由恒佳生物技术(苏州)有限公司提供，是基于BALB/c裸鼠建立的786-O肿瘤皮下异位移植瘤模型，该模型为人肾透明细胞腺癌细胞构建的小鼠模型。随机选取该动物模型2只，每只给予上述 68Ga-NYM005药物100μCi，给扫描前采用适当浓度的异氟烷/氧气混合气体进行预麻醉之后，将动物放置于西门子Inveon小动物PET/CT扫描床上，并使用异氟烷/氧气混合气体持续麻醉，于给药后1h进行10min PET扫描，经设备软件自动重建数据后获得扫描图像，利用PMOD软件对扫描图像进行分析。如图5所示(箭头处为肿瘤处)，通过对扫描数据进行分析， 68Ga-NYM005药物在肿瘤位置富集程度高，说明该药物具有良好的肿瘤靶向性，未被肿瘤摄取的药物通过肾脏-膀胱快速排出体外。
实施例6  68Ga-NYM005药物在OS-RC-2荷瘤鼠模型上的显像结果
实验动物OS-RC-2模型由恒佳生物技术(苏州)有限公司提供，是基于BALB/c裸鼠建立的OS-RC-2肿瘤皮下异位移植瘤模型，该模型为人肾癌细胞构建的小鼠模型。选取该动物模型2只，每只给予上述 68Ga-NYM005药物100μCi，扫描前采用适当浓度的异氟烷/空气混合气体进行预麻醉之后，将动物放置于MicroPET/CT影像舱(SNPC-303型Super Nova，平生医疗科技(昆山)有限公司)内，并使用异氟烷/空气混合气体维持麻醉，于给药后1h进行MicroPET/CT扫描，经设备软件重建后获得扫描图像，利用PMOD软件对扫描图像进行分析。结果如图6所示(箭头处为肿瘤摄取处)， 68Ga-NYM005药物在肿瘤位置富集程度高，说明该药物具有良好的肿瘤靶向性，未被肿瘤摄取的药物通过肾脏-膀胱快速 排出体外。
实施例7  68Ga-NYM005药物在786-O荷瘤鼠模型上PET/CT扫描组织分布及靶向性实验
实验动物786-O模型由上海标度百奥生物技术有限公司提供，是基于NOD-SCID鼠建立的786-O肿瘤皮下异位移植瘤模型，该模型为人肾透明细胞腺癌细胞构建的小鼠模型。选取该动物模型2只，每只给予上述 68Ga-NYM005药物100μCi，扫描前采用适当浓度的异氟烷/空气混合气体进行预麻醉之后，将动物放置于MicroPET/CT影像舱(SNPC-303型Super Nova，平生医疗科技(昆山)有限公司)内，并使用异氟烷/空气混合气体维持麻醉，于给药后1h进行MicroPET/CT扫描，经设备软件重建后获得扫描图像，利用PMOD软件对扫描图像进行分析。结果如图7所示(箭头处为肿瘤处)， 68Ga-NYM005药物在786-O肿瘤模型鼠体内生物分布显示其主要通过肾-膀胱排泄出体外，在肿瘤组织有高放射性浓聚，在其他组织中摄取较低。
实施例8  68Ga-NYM005药物在786-0鼠模型上竞争抑制实验
实验动物786-O模型由上海标度百奥生物技术有限公司提供，是基于NOD-SCID鼠建立的786-O肿瘤皮下异位移植瘤模型，该模型为人肾透明细胞腺癌细胞构建的小鼠模型。随机选取该动物模型2只，小鼠尾静脉注射冷药NYM0005，注射剂量为注射热药( 68Ga-NYM0005)量的40倍，给药顺序为给冷药后30min注射热药 68Ga-NYM0005，扫描前采用适当浓度的异氟烷/空气混合气体进行预麻醉之后，将动物放置于MicroPET/CT影像舱(SNPC-303型Super Nova，平生医疗科技(昆山)有限公司)内，并使用异氟烷/空气混合气体维持麻醉，于给热药后1h进行MicroPET/CT扫描，经设备软件重建后获得扫描图像，利用PMOD软件对扫描图像进行分析。结果如图8所示(箭头处为肿瘤处)，加入冷药能明显阻断肿瘤对 68Ga-NYM005的摄取，从而证实肿瘤对 68Ga-NYM005的摄取为特异性靶向摄取。
实施例9 ICR小鼠组织分布实验及小鼠血药代实验
4-6周龄雌性ICR小鼠购自恒佳生物技术(苏州)有限公司。随机选取上述ICR鼠4只，每只给予上述 68Ga-NYM005药物50μCi，分别于给药后5min、15min、30min、45min、60min、2h、3h、4h点颌下取血测伽马计数，计算不同时间点的血药浓度，再利用药代计数软件DAS计算非房室模型药代参数(如表2)。结果如图9所示，药代计算结果为消除 半衰期t1/2z＝5.81h，达峰时间Tmax约为0.0833h，峰浓度Cmax约为225.6ug/L，药代活性良好。
表2基于药代计数软件DAS计算的非房室模型药代参数
统计矩参数 单位 参数值
AUC(0-t) ug/L*h 250.408
AUC(0-∞) ug/L*h 581.348
AUMC(0-t)   372.384
AUMC(0-∞)   4470.84
MRT(0-t) h 1.487
MRT(0-∞) h 7.69
VRT(0-t) h^2 1.593
VRT(0-∞) h^2 69.821
Zeta 1/h 0.119
Zeta回归尾点   124
Cz(尾点回归值) ug/L 39.471
t1/2z h 5.81
Tmax h 0.0833333
Vz L/kg 0.588
CLz L/h/kg 0.07
Cmax ug/L 225.6085
实施例10  68Ga-NYM005在HT29、PC3、U87模型PET扫描组织分布及靶向性实验
实验动物HT29、PC3、U87模型由恒佳生物技术(苏州)有限公司提供，是基于BALB/c裸鼠建立的HT29、PC3、U87肿瘤皮下异位移植瘤模型，分别为人结肠癌细胞、人前列腺癌细胞、人脑胶质瘤构建的小鼠模型。随机选取以上动物模型各1只，每只给予上述 68Ga-NYM005药物80μCi，扫描前采用适当浓度的异氟烷/氧气混合气体进行预麻醉之后，将动物放置于平生医疗Super Nova小动物PET/CT小动物PET/CT扫描舱内，并使用异氟烷/氧气混合气体持续麻醉，于给药后1h进行MicroPET/CT扫描，经设备软件重建后获得扫描图像，利用PMOD软件对扫描图像进行分析。结果如图10所示(箭头处为肿瘤处)， 68Ga-NYM005药物在肿瘤位置无明显高摄取，说明 68Ga-NYM005药物在HT29、PC3、U87这些肿瘤中无靶向性。
实施例11  68Ga-NYM005在HCT116模型PET/CT扫描组织分布及靶向性实验
实验动物HCT116模型由恒佳生物技术(苏州)有限公司提供，是基于BALB/c裸鼠建立的HCT116肿瘤皮下异位移植瘤模型，该模型为人结肠癌细胞构建的小鼠模型。选取该动物模型2只，每只给予上述 68Ga-NYM005药物100μCi，扫描前采用适当浓度的异氟烷/空气混合气体进行预麻醉之后，将动物放置于MicroPET/CT影像舱(SNPC-303型Super Nova，平生医疗科技(昆山)有限公司)内，并使用异氟烷/空气混合气体维持麻醉，于给药后1h进行MicroPET/CT扫描，经设备软件重建后获得扫描图像，利用PMOD软件对扫描图像进行分析。结果如图11所示(箭头处为肿瘤处)， 68Ga-NYM005药物在肿瘤位置无明显高摄取，说明 68Ga-NYM005药物在HCT116肿瘤中无靶向性。
实施例12安全性评价实验
按照医院科研临床伦理对于正电子示踪剂药物毒性评价要求，实验动物选择ICR小鼠6只，供应商为麦睿可(苏州)科技服务有限公司，每只动物给予300μCi  68Ga-NYM005无菌注射液，给药完后进行连续7天观察。结果如图12所示，在7天观察中，所有小鼠无死亡，无异常反应，且实验完成后体重均有增加。 68Ga-NYM005分子安全性良好，满足科研临床用药需求。
实施例13  68Ga-NYM005人体内照射剂量估算内照射剂量估算
取ICR小鼠3只，每只给予100μCi放射性药物 68Ga-NYM005后进行动态30min扫描，然后在1h、2h、3h、4h时间点进行10min静态扫描，根据扫描数据可获得正常小鼠体内不同时间点的组织分布数据，进而根据PMOD软件计算出小鼠体内各脏器的滞留时间，再从小鼠体内各脏器的滞留时间推算到人体脏器的滞留时间，再用OLINDA软件计算出人体内照射剂量，计算结果为人体整体有效剂量ED＝0.011mSv/MBq，按临床给药剂量111MBq(3mCi)/人计算，总辐射有效剂量1.221mSv/人，远低于常规CT胸腹部扫描时10-15mSv的剂量，在安全范围内，辐射剂量估算表下表3。
表3科研临床患者各组织器官内照射剂量计算
Figure PCTCN2022125512-appb-000041
Figure PCTCN2022125512-appb-000042
实施例14  68Ga-NYM005科研临床实验显像结果
患者经目前常用肿瘤早期筛查示踪剂18F-FDG PEC/CT显像提示右肾占位，双肺及纵隔淋巴结转移，后右肾穿刺活检，病理提示：透明细胞癌，WHO/ISUP核分级2级，Vimentin9+，PAX-8+，P504S+，Ki67 10％。经临床医生推荐入组并签订《知情同意书》后，经手背静脉给予 68Ga-NYM005无菌注射液5mCi后，等待1h行PET/CT扫描，影像结果见图13。
检查结果分析：右肾可见一软组织密度肿物，大小约9.2cm，放射性摄取异常增高，SUVmax 14.6。下腔静脉内可见条形放射性摄取增高灶，长约4.7cm，SUVmax 12.7。部分肺血管内可见条样放射性摄取增高，SUVmax 3.4。左侧腹膜后、左肺门、主肺动脉窗、左侧锁骨上可见多发放射性摄取增高的淋巴结，最大者约1.8cm，SUVmax 12.5。肺内可见多 发软组织密度结节，最大者约2.5cm，放射性摄取增高，SUVmax 11.6。左侧股骨头可见一放射性摄取增高灶，约1.4cm，SUVmax 11.1。
临床诊断结论：右肾 68Ga-NYM005高表达病灶，可符合肾透明细胞癌表现，伴左侧腹膜后、左肺门、主肺动脉窗、左侧锁骨上多发淋巴结转移，肺内多发转移，左侧股骨头转移，下腔静脉及肺动脉内瘤栓形成。
通过该临床验证， 68Ga-NYM005分子在肾癌诊断临床应用上比目前常用18F-FDG示踪剂能发现更多的肿瘤转移灶，更有临床应用价值。
实施例15 NYM034分子的制备过程
Figure PCTCN2022125512-appb-000043
NYM034结构式
其LC-MS谱图见图14，HPLC谱图见图15。
合成路线:
Figure PCTCN2022125512-appb-000044
多肽的合成:多肽的合成采用Fmoc合成法
1.树脂制备:将含有Fmoc-Asp-Alloc(500μmol,1.00eq)和DIEA(2.00mmol,4.00eq)的DCM溶液10.0mL加入2-CTC树脂(500μmol,1.00eq)，20℃下氮气吹扫，反应搅拌2小时，再加入MeOH(500μL)继续搅拌30.0min，随后用DMF(20.0mL*5)洗涤树脂，洗 涤五次，每次使用DMF 20.0mL。
2.脱保护:将含有20％哌啶的DMF(20.0mL)溶液加入到树脂内，在氮气吹扫下搅拌30.0min，用DMF(20.0mL*5)洗涤过滤树脂，洗涤五次，每次使用DMF 20.0mL。
3.偶联：在DMF(20.0mL)溶剂内加入5-叠氮戊酸(1.50mmol,3.00eq))，并加入HATU(1.50mmol,3.00eq)和DIEA(3.00mmol,6.00eq)，将混合物加入到树脂内，在20℃下，氮气吹扫下搅拌30.0min，用DMF(20.0mL*5)洗涤树脂，洗涤五次，每次使用DMF 20.0mL。
4.重复上述步骤2至3，依次偶联表4中的氨基酸:
表4
投料氨基酸 偶联试剂
化合物3b(1.50eq) CuI(0.50eq)、DIEA(2.00eq)
N-Fmoc-1,4-diaminobutane HCL(3.00eq) HOAt(3.00eq)、DIC(3.00eq)
DOTA-(COOt-Bu) 3(1.50eq) HOAt(1.50eq)、DIC(1.50eq)
5.用DMF(20.0mL*5)洗涤树脂，洗涤五次，每次使用DMF 20.0mL，过滤得到多肽树脂(5b)。
6.多肽的裂解和纯化：
用MeOH(20.0mL*3)洗涤上步骤树脂，洗涤三次，每次使用MeOH 20.0mL，真空干燥，得到多肽树脂(5b)。
将带有侧链保护基的多肽加入到烧瓶内，并添加20mL裂解缓冲液((92.5％TFA/2.5％TIS/2.5％H2O/2.5％MPR)，20℃下搅拌2小时进行脱保护；用叔丁基甲基醚(50.0mL)沉淀并离心(3.00min，3000rpm)，再用叔丁基甲基醚洗涤沉淀两次(50.0ml)。
将得到的粗肽真空干燥2小时，得到400mg粗产物。
用制备-高效液相色谱法(TFA条件:A:0.075％TFA的H2O溶液,B:ACN)纯化，得到目标产物NYM034(62.0mg,55.3umol，产率11.1％，纯度98.45％，TFA)，白色固体。
实施例16  68Ga-NYM034分子的制备过程
合成的NYM034前体经与放射性核素镓[ 68Ga]螯合反应进一步获得可用于临床PET/CT示踪的 68Ga-NYM034示踪剂，其标记技术成熟，通常标记产物放射性化合物化学纯度可达到99％。
标记过程如下所示，全部标记过程可以在20min内完成，放射性化合物产率可达到 70％。
Figure PCTCN2022125512-appb-000045
68Ga核素经0.05M盐酸溶液淋洗锗镓发生器获得，取1mL该 68Ga核素(20mCi)溶液加入到反应瓶中，然后再加入1mL 0.3mol/L醋酸/醋酸钠缓冲溶液加入到反应瓶中，使 68Ga核素体积与缓冲溶液体积比为1：1，调节pH值为4.0。取NYM034前体化合物适量加入到灭菌注射用水中配制成1mg/mL的前体溶液，然后取45nmol(44.5ug)加入到反应瓶中，于105度下反应6min，反应完成后冷却1min，用10mL无菌注射器取5mL灭菌注射用水加入到反应瓶中稀释反应液并达到降低反应液温度的目的，再将反应瓶内全部液体抽到注射器内，取出预先活化的Sep-Pak C-18小柱接到注射器出口端，推动反应稀释液流经Sep-Pak C-18小柱，目标产物 68Ga-NYM034被C-18小柱吸附，然后用1mL 70％医用级无水乙醇溶液淋洗C-18小柱，淋洗液经0.22μm无菌滤膜过滤后流入无菌真空瓶内，再加入4mL生理盐水溶液，即得 68Ga-NYM034无菌注射液。
使用放射性薄层色谱法对上述产品进行质控，载体为玻璃纤维纸，展开剂为0.5M柠檬酸/柠檬酸钠缓冲液(pH＝5)。取玻璃纤维纸，用移液枪移取样品轻轻点在玻璃纤维纸距离底部1.5cm处，放入事先加入500μL 0.5M柠檬酸/柠檬酸钠缓冲液(pH＝5)试管中，展开到距离色谱纸顶部2.5cm处取出晾干，Radio-TLC薄层扫描仪检测。在0.5M柠檬酸/柠檬酸钠缓冲液(pH＝5)体系下，产物的Rf值在0.3-0.6之间。如图16所示， 68Ga-NYM034分子放射性薄层色谱扫描纯度分析结果，放射性化合物化学纯度100％。
实施例17  68Ga-NYM034 786-O、OS-RC-2模型PET扫描组织分布及靶向性实验
实验动物786-O模型由恒佳生物技术(苏州)有限公司提供，是基于BALB/c裸鼠建立的786-O肿瘤皮下异位移植瘤模型，该模型为人肾透明细胞腺癌细胞构建的小鼠模型。实验动物OS-RC-2模型由恒佳生物技术(苏州)有限公司提供，是基于BALB/c裸鼠建立的OS-RC-2肿瘤皮下异位移植瘤模型，该模型为人肾癌细胞构建的小鼠模型。分别选取2种动物模型各1只，每只给予上述 68Ga-NYM034药物100μCi，扫描前采用适当浓度的异氟烷/空气混合气体进行预麻醉之后，将动物放置于MicroPET/CT影像舱(SNPC-303型Super Nova，平生医疗科技(昆山)有限公司)内，并使用异氟烷/空气混合气体维持麻醉，于给药后1h进行MicroPET/CT扫描，经设备软件重建后获得扫描图像，利用PMOD软件对 扫描图像进行分析。结果如图17所示(箭头处为肿瘤处)， 68Ga-NYM034药物在OS-RC-2模型肿瘤位置富集程度高，而在786-O模型肿瘤摄取较少，说明该药物在OS-RC-2模型种具有良好的肿瘤靶向性。
实施例18 NYM035分子的制备过程
Figure PCTCN2022125512-appb-000046
NYM035结构式
其LC-MS谱图见图18，HPLC谱图见图19。
合成路线：
步骤一：
Figure PCTCN2022125512-appb-000047
将含有化合物(1a)(3.00g,16.7mmol,1.00eq)和吡啶(2.63g,33.3mmol,2.69mL,2.00eq)溶于30.0mL的DMF溶剂，溶液冷却至0℃；将化合物(4a)(2.97g,16.65mmol,1.00eq)溶于20.0mL的DMF溶剂，并将此溶液逐滴加入到前述溶液内，并在25℃下搅拌14.0小时。将反应的溶液减压浓缩去除溶剂，残留物用45.0mL水和45.0mL饱和NaHCO 3稀释，过滤得到化合物(2a)(5.00g,15.0mmol)，为白色固体。
步骤二：
Figure PCTCN2022125512-appb-000048
将化合物(2a)(5.00g,15.0mmol，1.00eq)和NaOH(3.45g,86.3mmol,5.76eq)溶于70.0mL水中，搅拌加热1小时至60℃。反应溶液冷却后用1mol/L HCl溶液调节pH 4。所得固体经过滤水洗得到化合物(3a)(2.00g,6.22mmol)，为白色固体。
步骤三：
Figure PCTCN2022125512-appb-000049
多肽合成:多肽的合成采用Fmoc合成法
1.树脂制备:将Fmoc-Asp-Alloc(500μmol,1.00eq)、DIEA(2.00mmol,4.00eq)溶于10.0mLDCM溶剂内，此溶液加入2-CTC树脂，20℃下N 2吹扫，反应搅拌2小时。然后加入MeOH(500μL)继续搅拌30.0min，随后用DMF(20.0mL*5)洗涤树脂，洗涤五次，每次使用DMF 20.0mL。
2.脱保护:将含有20％哌啶的DMF(20.0mL)溶液加入到树脂内，在N 2吹扫下搅拌30.0min，用DMF(20.0mL*5)洗涤过滤树脂，洗涤五次，每次使用DMF 20.0mL。
3.偶联：Fmoc-5-Ava-OH(0.75mmol,1.50eq)溶于20.0mLDMF溶剂内，向此溶液内加入HOAt(0.75mmol,1.50eq)和DIC(0.75mmol,1.50eq)，将混合物加入到树脂内，在20℃下，氮气吹扫下搅拌2小时，用DMF(20.0mL*5)洗涤树脂，洗涤五次，每次使用DMF20.0mL。
4.重复上述步骤2至3，偶联表5中的氨基酸:
表5
投料氨基酸 偶联试剂
化合物(3a)(1.50eq) HOAt(1.50eq)and DIC(1.50eq)
Fmoc-Dab.HCl(3.00eq) HOAt(3.00eq)and DIC(3.00eq)
DOTA-(COOt-Bu) 3(1.50eq) HOAt(1.50eq)and DIC(1.50eq)
5.用DMF(20.0mL*5)洗涤树脂，过滤得到多肽树脂(5a)，洗涤五次，每次使用DMF20.0mL。
6.多肽的裂解和纯化：
用MeOH(20.0mL*3)洗涤，洗涤三次，每次使用MeOH 20.0mL，真空干燥，得到多肽树脂(5a)。
将带有侧链保护基的多肽(5a)加入到烧瓶内，并添加20mL裂解缓冲液(92.5％TFA/2.5％TIS/2.5％H2O/2.5％MPR)，20℃下搅拌2小时进行脱保护；用叔丁基甲基醚(50.0mL)沉淀并离心(3.00min，3000rpm)，再用叔丁基甲基醚洗涤沉淀两次(50.0ml)。
将得到的粗肽真空干燥2小时，得到400mg粗产物。
经制备-高效液相色谱(TFA条件:A:0.075％TFA的H2O溶液,B:ACN)纯化，得到目标产物NYM035(80.0mg,72.2umol，产率14.4％，纯度98.68％)，为白色固体。
实施例19  68Ga-NYM035分子的制备过程
合成的NYM035前体经与放射性核素镓[ 68Ga]螯合反应进一步获得可用于临床PET/CT示踪的 68Ga-NYM035示踪剂，其标记技术成熟，通常标记产物放射性化合物化学纯度可达到99％。
标记过程如下所示，全部标记过程可以在20min内完成，放射性化合物产率可达到70％。
Figure PCTCN2022125512-appb-000050
本实施例的 68Ga标记NYM035的方法，具体步骤如下： 68Ga核素经0.05M盐酸溶液淋洗锗镓发生器获得，取1mL该 68Ga核素(20mCi)溶液加入到反应瓶中，然后再加入1mL 0.3mol/L醋酸/醋酸钠缓冲溶液加入到反应瓶中，使 68Ga核素体积与缓冲溶液体积比为1：1，调节pH值为4.0。取NYM035前体化合物适量加入到灭菌注射用水中配制成1mg/mL的前体溶液，然后取45nmol(44ug)加入到反应瓶中，于105℃下反应6min，反应完成后冷却1min，用10mL无菌注射器取5mL灭菌注射用水加入到反应瓶中稀释反应液并 达到降低反应液温度的目的，再将反应瓶内全部液体抽到注射器内，取出预先活化的Sep-Pak C-18小柱接到注射器出口端，推动反应稀释液流经Sep-Pak C-18小柱，目标产物 68Ga-NYM035被C-18小柱吸附，然后用1mL 70％医用级无水乙醇溶液淋洗C-18小柱，淋洗液经0.22μm无菌滤膜过滤后流入无菌真空瓶内，再加入4mL生理盐水溶液，即得 68Ga-NYM035无菌注射液。
使用放射性薄层色谱法对上述产品进行质控，载体为玻璃纤维纸，展开剂为0.5M柠檬酸/柠檬酸钠缓冲液(pH＝5)。取玻璃纤维纸，用移液枪移取样品轻轻点在玻璃纤维纸距离底部1.5cm处，放入事先加入500μL 0.5M柠檬酸/柠檬酸钠缓冲液(pH＝5)试管中，展开到距离色谱纸顶部2.5cm处取出晾干，Radio-TLC薄层扫描仪检测。在0.5M柠檬酸/柠檬酸钠缓冲液(pH＝5)体系下，产物的Rf值在0.3-0.6之间。如图20所示， 68Ga-NYM035分子放射性薄层色谱扫描纯度分析结果，放射性化合物化学纯度100％。
实施例20 68Ga-NYM035 786-O、OS-RC-2模型PET扫描组织分布及靶向性实验
实验动物786-O模型由恒佳生物技术(苏州)有限公司提供，是基于BALB/c裸鼠建立的786-O肿瘤皮下异位移植瘤模型，该模型为人肾透明细胞腺癌细胞构建的小鼠模型。实验动物OS-RC-2模型由恒佳生物技术(苏州)有限公司提供，是基于BALB/c裸鼠建立的OS-RC-2肿瘤皮下异位移植瘤模型，该模型为人肾癌细胞构建的小鼠模型。分别选取2种动物模型各1只，每只给予上述 68Ga-NYM035药物100μCi，扫描前采用适当浓度的异氟烷/空气混合气体进行预麻醉之后，将动物放置于MicroPET/CT影像舱(SNPC-303型Super Nova，平生医疗科技(昆山)有限公司)内，并使用异氟烷/空气混合气体维持麻醉，于给药后1h进行MicroPET/CT扫描，经设备软件重建后获得扫描图像，利用PMOD软件对扫描图像进行分析。结果如图21所示(箭头处为肿瘤处)， 68Ga-NYM035药物在OS-RC-2模型肿瘤位置富集程度高，而在786-O模型肿瘤摄取较少，说明该药物在OS-RC-2模型种具有良好的肿瘤靶向性。
实施例21荧光扫描实验及荧光导航解剖实验
选取人肾透明细胞腺癌细胞构建小鼠模型，建立异位移植瘤模型。随机选取该动物模型，给予一定量的本申请的带有荧光基团分子药物化合物(6)-(11)、化合物(15)-(18)，于给药后30min-120h之间进行活体荧光扫描成像，扫描时采用适当浓度的异氟烷/空气混合气体进行预麻醉和维持麻醉，带有荧光基团的分子药物在肿瘤模型鼠体内肿瘤组织处有高荧光浓聚，在其他组织中荧光浓聚较低。
选取上述小鼠模型，进行给药，约24h后在荧光观察下进行常规脏器解剖。药物在肿瘤模型鼠体内生物分布显示其主要通过肾脏排泄出体外，在肿瘤组织有高荧光浓聚，在其他组织中荧光浓聚较低。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。

Claims (15)

  1. 一种化合物或其药学上可接受的盐、酯或溶剂化物，其特征在于，其结构如式(I)所示，
    Figure PCTCN2022125512-appb-100001
    其中，X为任选取代的5-6元杂环基、环烷基、二唑基、三唑基或酰胺基；
    Y为
    Figure PCTCN2022125512-appb-100002
    任选取代的
    Figure PCTCN2022125512-appb-100003
    -COOH、
    Figure PCTCN2022125512-appb-100004
    任选取代的
    Figure PCTCN2022125512-appb-100005
    -OH、-CH(CH 3)OH、水溶性氨基酸、螯合基团或荧光基团；
    Z为H、螯合基团或荧光基团；
    Y、Z至少有一个为螯合基团或荧光基团；
    L 1、L 2、L 3分别选自聚乙二醇链、亲水性氨基酸链、碳链或-(CH 2)nCONH-；
    R 1选自被磺酸氨基取代的5-12元杂芳基，
    n为1～6之间的整数。
  2. 一种化合物或其药学上可接受的盐、酯或溶剂化物，其特征在于，其结构如式(II)所示，
    Figure PCTCN2022125512-appb-100006
    其中，
    n为1或2；
    X为5-6元杂环基、环烷基、二唑基、三唑基或酰胺基；
    Y’为
    Figure PCTCN2022125512-appb-100007
    任选取代的
    Figure PCTCN2022125512-appb-100008
    -COOH、
    Figure PCTCN2022125512-appb-100009
    任选取代的
    Figure PCTCN2022125512-appb-100010
    -OH、-CH(CH 3)OH、水溶性氨基酸、螯合基团或荧光基团；
    Z为H、螯合基团或荧光基团；
    Y’、Z至少有一个为螯合基团或荧光基团。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐、酯或溶剂化物，其特征在于，
    X为
    Figure PCTCN2022125512-appb-100011
    任选地，所述螯合基团选自1,4,7,10-四氮杂环十二烷-N,N`,N``,N```,-四乙酸、1,4,7-三氮杂环壬烷-1,4,7-三乙酸、2-(4,7-双(羧甲基)-1,4,7-三偶氮壬-1-基)戊二酸、2-(4,7,10-三(羧甲基)-1,4,7,10-四氮杂环十二烷-1-基)戊二酸、1,4,7-三氮杂环壬烷次膦酸、1,4,7-三氮杂环壬烷-1-[甲基(2-羧乙基)次膦酸]-4,7-双[甲基(2-羧甲基)次膦酸]、N’-{5-[乙酰基(羟基)氨基]戊基}-N-[5-({4-[5-氨基戊基)(羟基)氨基]-4-氧丁酰基}氨基)戊基]-N-羟基琥珀酰胺、二乙三胺五乙酸、反式-环己基-二乙三胺五乙酸、对异氰硫基苄基-二乙三胺五乙酸、1-(异氰硫基苄基)-3-甲基-二乙三胺五乙酸、1-(异氰硫基苄基)-4-甲基-二乙三胺五乙酸、1-(2)-甲基-4-异氰基苄基-二乙三胺五乙酸、1-氧杂-4,7,10-三氮杂环十二烷-4,7,10-三乙酸、6-肼基烟酸琥珀酰亚胺酯盐酸盐和巯基乙酰基三甘氨酸；
    任选地，所述荧光基团选自花青素类荧光染料；
    任选地，所述荧光基团选自
    Figure PCTCN2022125512-appb-100012
    Figure PCTCN2022125512-appb-100013
  4. 一种化合物或其药学上可接受的盐、酯或溶剂化物，其特征在于，其结构选自如下一种：
    Figure PCTCN2022125512-appb-100014
    Figure PCTCN2022125512-appb-100015
    Figure PCTCN2022125512-appb-100016
    Figure PCTCN2022125512-appb-100017
  5. 一种化合物，其特征在于，所述化合物由权利要求1-4任一项所述的化合物或其药学上可接受的盐、酯或溶剂化物与放射性核素或非放射性元素共价而成。
  6. 根据权利要求5所述的化合物，其特征在于，所述放射性核素选自 68Ga、 18F、 99mTc、 89Zr、 111In、 45Ti、 59Fe、 64Cu、 94mTc、 67Ga、 71/72/74As、 43/44Sc、 82mRb、 52Mn、 86Y、 125I、 124I、 76Br、 177Lu、 90Y、 131I、 153Sm、 67Cu、 89Sr、 137Cs、 166Ho、 177Yb、 105Rh、 186/188Re、 47Sc、 212/213Bi、 225Ac、 212Pb、 149Pm、 211At、 223Ra和 227Th；
    任选地，所述非放射性元素选自Ga、Fe和Gd；
    任选地，所述放射性核素选自 18F；
    任选地，所述放射性核素 18F络合是通过放射性同位素氟化铝形成的。
  7. 一种化合物，其结构选自如下之一：
    Figure PCTCN2022125512-appb-100018
    Figure PCTCN2022125512-appb-100019
    Figure PCTCN2022125512-appb-100020
    Figure PCTCN2022125512-appb-100021
    Figure PCTCN2022125512-appb-100022
    Figure PCTCN2022125512-appb-100023
  8. 一种药物组合物，其特征在于，所述药物组合物包含权利要求1-7任一项所述的化合物，或其药学上可接受的盐、酯或溶剂化物，和药学上可接受的载体、辅料。
  9. 权利要求1-7任一项所述的化合物或其药学上可接受的盐、酯或溶剂化物或权利要求8所述的药物组合物在制备用于诊断和/或治疗一种或多种表达碳酸酐酶IX的肿瘤、癌症或细胞的试剂和/或药物中的用途。
  10. 根据权利要求9所述的用途，其特征在于，所述诊断的形式选自光学成像和/或核素成像；
    任选地，所述诊断的形式选自荧光显像、PET成像和/或SPECT成像；
    任选地，所述治疗选自放射性治疗和/或辅助手术开展荧光手术导航；
    任选地，所述肿瘤、癌症选自肾癌、脑胶质瘤及其他实体瘤和/或其转移病灶。
  11. 权利要求1-7任一项所述的化合物或其药学上可接受的盐、酯或溶剂化物或权利要求8所述的药物组合物，用于诊断和/或治疗表达碳酸酐酶IX的肿瘤、癌症或细胞。
  12. 权利要求1-7任一项所述的化合物或其药学上可接受的盐、酯或溶剂化物或权利要求8所述的药物组合物，用于诊断和/或治疗肾癌、脑胶质瘤及其他实体瘤和/或其转移病灶。
  13. 一种诊断和/或治疗表达碳酸酐酶IX的肿瘤、癌症或细胞的方法，其特征在于，给与患者药学上可接受剂量的权利要求1-7任一项所述的化合物或其药学上可接受的盐、酯或溶剂化物或权利要求8所述的药物组合物。
  14. 根据权利要求13所述的方法，其特征在于，所述表达碳酸酐酶IX的相关疾病为肾癌、脑胶质瘤及其他实体瘤和/或其转移病灶。
  15. 一种试剂盒，其特征在于，所述试剂盒包含权利要求1-7任一项所述的化合物或其药学上可接受的盐、酯或溶剂化物。
PCT/CN2022/125512 2022-02-15 2022-10-14 碳酸酐酶ix靶向放射性诊疗药物及其制备方法 WO2023155454A1 (zh)

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