Carbonic anhydrase ix targeting radio-diagnostic and therapeutic drugs and methods of making the same

Abstract

The present application relates to carbonic anhydrase IX targeted radio-diagnostic and therapeutic drugs and preparation methods thereof, and in particular, the present application relates to a compound or a pharmaceutically acceptable salt, ester or solvate thereof, the structure of which is shown as formula (I), the compound can be used for diagnosing and / or treating one or more tumors, cancers or cells expressing carbonic anhydrase IX

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to carbonic anhydrase (CA)IX targeted radiotherapeutic drugs and their preparation methods, and more specifically to compounds of formula (I) or formula (II) or their pharmaceutically acceptable salts, esters or solvates, complexes, pharmaceutical compositions and their uses. Background Technology

[0002] 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. Loss of VHL subsequently leads to overexpression of carbonic anhydrase IX (CAIX) (Bragmaier et al., 2004; 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.

[0003] CAIX has limited expression in normal tissues and organs other than the gastrointestinal tract, gallbladder, and pancreatic duct. No CAIX expression has been reported in normal renal parenchyma or benign renal masses. The feasibility of non-invasive diagnosis of ccRCC based on CAIX expression has been demonstrated using the radiolabeled antibody G250. However, antibodies as molecular imaging agents are pharmacokineticly limited, including slow blood and non-target tissue clearance (typically 2-5 days or longer) and non-specific organ uptake. Low molecular weight (LMW) agents have demonstrated faster pharmacokinetics and higher specificity within the clinically convenient time following administration. They also offer site-specific radiolabeling typically achieved through a wider range of chemical methods and radionuclides, and may provide a shorter regulatory approval pathway.

[0004] Therefore, there is a growing need for targeted radiotherapeutic drugs targeting CAIX to be developed and applied. Summary of the Invention

[0005] In a first aspect, the present invention provides a compound or a pharmaceutically acceptable salt, ester or solvation thereof having the structure shown in formula (I).

[0006]

[0007] Wherein, X is an optionally substituted 5-6 membered cycloalkyl, heterocyclic, diazolyl, triazolyl, or amide group;

[0008] Y is Optional replacement -COOH, Optional replacement -OH, -CH(CH3)OH, water-soluble amino acids, chelating groups or fluorescent groups;

[0009] Z can be H, a chelating group, or a fluorescent group;

[0010] At least one of Y and Z is a chelating group or a fluorescent group;

[0011] L1, L2, and L3 are selected from polyethylene glycol chains, hydrophilic amino acid chains, carbon chains, or -(CH2)nCONH-, respectively;

[0012] R1 is selected from 5-12 heteroaryl groups substituted with sulfonic acid amino groups;

[0013] n is an integer between 1 and 6.

[0014] This invention provides a compound or a pharmaceutically acceptable salt, ester or solvation thereof, having the structure shown in formula (I).

[0015]

[0016] Wherein, X is selected from 5-6 membered heterocyclic groups, diazole groups, triazole groups, and amide groups;

[0017] Y is selected from -OH, -CH(CH3)OH, water-soluble amino acids, chelating groups, and fluorescent groups;

[0018] Z is selected from H, chelating groups, and fluorescent groups;

[0019] L1, L2, and L3 are selected from polyethylene glycol chains, hydrophilic amino acid chains, and carbon chains, respectively.

[0020] R1 is selected from 5-12 heteroaryl groups obtained by sulfonic acid amino groups.

[0021] In some embodiments of the present invention, the aforementioned polyethylene glycol chain is a chain formed by one or more polyethylene glycol units (-O-(CH2)2-O-), such as a chain formed by 1, 2, 3, 4, 5, 6, 7 or 8 polyethylene glycol units (-O-(CH2)2-O-), with other variables as defined in the present invention.

[0022] In some embodiments of the present invention, the aforementioned hydrophilic amino acid chain is a chain formed by the condensation of one or more identical or different hydrophilic amino acids, such as a chain formed by the condensation of 1, 2, 3, 4, 5, 6, 7 or 8 hydrophilic amino acids. The hydrophilic amino acid is a general term for amino acids with highly hydrophilic side chains. For example, hydrophilic amino acids include those selected from threonine (Thr), serine (Ser), cysteine ​​(Cys), asparagine (Asn), glutamine (Gln), tyrosine (Tyr), lysine (Lys), arginine (Arg), histidine (His), aspartic acid (Asp) or glutamic acid (Glu). Other variables are as defined in the present invention.

[0023] In some embodiments of the present invention, the carbon chain mentioned above refers to a carbon chain formed by one or more substituted or unsubstituted straight-chain alkyl or branched alkyl groups, such as a carbon chain formed by substituted or unsubstituted straight-chain alkyl or branched alkyl groups consisting of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and other variables as defined in the present invention.

[0024] In some embodiments of the present invention, R1 is selected from... like The remaining variables are as defined in this invention.

[0025] In another aspect of the invention, the invention also provides a compound or a pharmaceutically acceptable salt, ester, or solvate thereof, characterized in that its structure is as shown in formula (II).

[0026]

[0027] Wherein, X is a 5-6 membered heterocyclic group, cycloalkyl group, diazolyl group, triazolyl group or amide group;

[0028] Y' is Optional replacement -COOH, Optional replacement -OH, -CH(CH3)OH, water-soluble amino acids, chelating groups or fluorescent groups;

[0029] Z can be H, a chelating group, or a fluorescent group;

[0030] At least one of Y' and Z is a chelating group or a fluorescent group.

[0031] In another aspect of the invention, the invention also provides a compound or a pharmaceutically acceptable salt, ester, or solvate thereof, characterized in that its structure is as shown in formula (II).

[0032]

[0033] Wherein, X is selected from substituted 5-6 membered heterocyclic groups, diazole groups, triazole groups, and amide groups;

[0034] Y is selected from -OH, -CH(CH3)OH, water-soluble amino acids, chelating groups, and fluorescent groups;

[0035] Z is selected from H, chelating groups, or fluorescent groups.

[0036] In some embodiments of the present invention, X is selected from... The remaining variables are as defined in this invention.

[0037] In some embodiments of the present invention, X is selected from... The remaining variables are as defined in this invention.

[0038] In some embodiments of the present invention, the 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-triazonon-1-yl)glutaric acid, 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid, 1,4,7-triazacyclononanephosphonic acid, 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-carboxymethyl)phosphonic acid], N'-{5-[acetyl(hydroxy)amino] The following are included: [4-[5-aminopentyl]-N-[5-({4-[5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide, diethylenetriaminepentaacetic acid, trans-cyclohexyl-diethylenetriaminepentaacetic acid, p-isocyanothiobenzyl-diethylenetriaminepentaacetic acid, 1-(isocyanothiobenzyl)-3-methyl-diethylenetriaminepentaacetic acid, 1-(isocyanothiobenzyl)-4-methyl-diethylenetriaminepentaacetic acid, 1-(2)-methyl-4-isocyanobenzyl-diethylenetriaminepentaacetic acid, 1-oxa-4,7,10-triazacyclododecane-4,7,10-triacetic acid, 6-hydrazylnicotinic acid succinimide hydrochloride, and mercaptoacetyl triglycine, with the remaining variables as defined in this invention.

[0039] In some embodiments of the present invention, the fluorescent group is selected from anthocyanin fluorescent dyes, including non-sulfonated anthocyanin dyes and sulfonated anthocyanin dyes, and the remaining variables are as defined in the present invention.

[0040] In some embodiments of the present invention, the anthocyanin fluorescent dye is selected from Cy3, Cy3.5, Cy5, Cy5.5, Cy7, Cy7.5, sulfonated-Cy3, sulfonated-Cy5, sulfonated-Cy7, or ICG, etc., and other variables are as defined in the present invention.

[0041] In some embodiments of the present invention, the fluorescent group is selected from...

[0042] In another aspect, the present invention also provides a compound or a pharmaceutically acceptable salt, ester or solvate thereof having a structure selected from the following:

[0043]

[0044]

[0045]

[0046]

[0047] In another aspect, the invention also provides a compound. According to embodiments of the invention, the compound is formed by covalently reacting the aforementioned compound or its pharmaceutically acceptable salt, ester, or solvate with a radioactive nuclide or a non-radioactive element.

[0048] In some embodiments of the present invention, 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.

[0049] In some embodiments of the present invention, the radionuclide is selected from... 131 I. According to an embodiment of the present invention, the labeling site is on the phenolic hydroxyl group of tyrosine, and can be used with other nuclides (such as... 68 Ga) can be simultaneously labeled to achieve both diagnostic and therapeutic functions on a single molecule.

[0050] In some embodiments of the present invention, the non-radioactive element is selected from Ga, Fe and Gd.

[0051] In some embodiments of the present invention, the radionuclide is selected from... 18 F.

[0052] In some embodiments of the present invention, the radionuclide 18 F complexes are formed through the radioactive isotope aluminum fluoride.

[0053] In another aspect, the present invention also provides a compound, wherein the structure of the compound is selected from one of the following:

[0054]

[0055]

[0056]

[0057]

[0058]

[0059] In another aspect, the present invention also provides a pharmaceutical composition. According to embodiments of the present invention, the pharmaceutical composition comprises the aforementioned compound, or a pharmaceutically acceptable salt, ester, or solvate thereof, and a pharmaceutically acceptable carrier, excipients, etc.

[0060] In another aspect of the invention, the invention also provides for the use of the foregoing compounds, or pharmaceutically acceptable salts, esters or solvates thereof, or the foregoing pharmaceutical compositions, in the preparation of reagents and / or medicaments for the diagnosis and / or treatment of one or more tumors, cancers or cells expressing carbonic anhydrase IX.

[0061] In some embodiments of the present invention, the form of the above-mentioned diagnosis is selected from optical imaging and / or radionuclide imaging.

[0062] In some embodiments of the present invention, the diagnostic methods described above are selected from fluorescence imaging, PET imaging, and / or SPECT imaging.

[0063] In some embodiments of the present invention, the above treatment is selected from radiotherapy and / or fluorescent surgical navigation to assist in surgery.

[0064] In some embodiments of the present invention, the tumors and cancers mentioned above are selected from renal cell carcinoma, glioma and other solid tumors and / or their metastatic lesions.

[0065] In another aspect, the invention also provides a kit. According to embodiments of the invention, the kit comprises the aforementioned compound, or a pharmaceutically acceptable salt, ester, or solvate thereof, or the aforementioned pharmaceutical composition.

[0066] In some embodiments of the present invention, the kit further comprises a pharmaceutically acceptable carrier, excipients, and other variables as defined in the present invention.

[0067] In some embodiments of the present invention, the pharmaceutically acceptable carriers and excipients described above include sterile water for injection, acetic acid / sodium acetate buffer solution, and sodium ascorbate.

[0068] In some embodiments of the present invention, the reagent kit is prepared by the following method:

[0069] 1) Prepare a precursor solution of the aforementioned compound at a concentration of 0.15-10 mg / mL using sterile water for injection as the solvent, and dispense it in vials at a concentration of 5-50 μg / vial;

[0070] 2) Prepare a 0.2-0.5 mol / L acetate / sodium acetate buffer solution (pH 3.5-4.5) using sterile water for injection as the solvent, and dispense it in 0.2-2 mL / bottles;

[0071] 3) Prepare a sodium ascorbate solution of 20-80 mg / mL using sterile water for injection as solvent, and dispense it in 0.1-1 mL / bottle.

[0072] In some embodiments of the present invention, all of the above solutions are processed under a clean bench that is Class C overall and Class A in some areas.

[0073] In another aspect, the present invention also provides the aforementioned kit for the diagnosis and / or treatment of one or more tumors or cancers expressing carbonic anhydrase IX. According to embodiments of the invention, the diagnostic method is selected from optical imaging and / or radionuclide imaging.

[0074] In some embodiments of the present invention, the diagnostic methods described above are selected from fluorescence imaging, PET imaging, and / or SPECT imaging.

[0075] In some embodiments of the present invention, the above treatment is selected from radiotherapy and / or fluorescent surgical navigation to assist in surgery.

[0076] In some embodiments of the present invention, the tumors and cancers mentioned above are selected from renal cell carcinoma, glioma and other solid tumors and / or their metastatic lesions.

[0077] According to embodiments of the present invention, the present invention has at least one of the following advantages over the prior art:

[0078] 1. The raw materials for synthesizing the compounds of this invention are easier to obtain, the synthesis process is simpler, and the yield is higher.

[0079] 2. The compound of the present invention uses water-soluble amino acids, with a simple molecular structure and small molecular weight, which facilitates the clearance of the molecule in normal tissues and organs, greatly reducing the internal radiation dose to patients during clinical applications, and at the same time, the process is simpler.

[0080] 3. The main molecular structure of the compound of this invention mainly uses amide bonds and amino acids, which allows the molecule to be synthesized using peptide solid-phase synthesis technology. At the same time, the molecular weight is small and the synthesis steps are few, which greatly reduces the difficulty of chemical composition production and control (CMC) in the IND new drug application process and further reduces the difficulty of impurity research.

[0081] 4. This invention optimizes the molecular structure by combining a large-molecule radionuclide chelating group with a carbonic anhydrase IX target group, achieving multiple functions on a single molecule. Based on current non-clinical and clinical trial results, the molecule shows good performance in radioactive diagnostic tracing (PET / CT or SPECT / CT scans) and good molecular safety.

[0082] 5. The compound structure of this invention further expands the suitable fluorescent groups. Fluorescent groups can be used to achieve fluorescence imaging and can further assist doctors in fluorescent surgical navigation (after the fluorescent group is targeted to the tumor along with the molecule, the tumor will fluoresce, while normal tissue will not fluoresce. Doctors can easily distinguish between healthy tissue and tumor tissue during surgery, which greatly improves the surgical effect).

[0083] Definitions and general terms

[0084] This invention will list in detail the relevant literature for the specific details described herein, and the embodiments are accompanied by diagrams of structural and chemical formulas. This invention is intended to cover all options, variations, and equivalents that may be included within the scope of this invention as defined in the claims. Those skilled in the art will recognize many similar or equivalent methods and substances described herein that can be applied in the practice of this invention. This invention is by no means limited to the description of methods and substances. Many documents and similar substances distinguish or conflict with this application, including but not limited to the definitions of terms, usage of terms, described techniques, or the scope controlled as defined in this application.

[0085] The following definitions will apply in this invention unless otherwise indicated. For the purposes of this invention, chemical elements are defined according to the periodic table, CAS version, and the Chemical Physics Handbook, 75. th Ed., 1994, defines it. Additionally, general principles of organic chemistry can be found in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito, 1999, and "March's Advanced Organic Chemistry," Michael B. Smith and Jerry March, John Wiley & Sons, New York, 2007. All of the above references are incorporated herein by reference.

[0086] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, or the specific examples, subclasses, and classes of compounds included in this invention as described in the embodiments. It should be understood that the term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted." Generally, the term "optionally," whether or not it precedes the term "substituted," indicates that one or more hydrogen atoms in the given structure may or may not be substituted by a specific substituent. Unless otherwise indicated, an optional substituent group may have one substituent substituted at each substituted position of the group. When more than one position in the given structural formula is substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. The substituents mentioned therein can be, but are not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, heteroaryloxy, oxo (=O), carboxyl, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyl-substituted alkoxy, etc.

[0087] Unless otherwise stated, the term "alkyl" means a saturated straight-chain or branched monovalent hydrocarbon group having 1-20 carbon atoms, or 1-10 carbon atoms, or 1-8 carbon atoms, or 1-6 carbon atoms, or 1-4 carbon atoms, or 1-3 carbon atoms, wherein the alkyl group may be independently and optionally substituted by one or more substituents described in this invention, including but not limited to, deuterium, amino, hydroxyl, cyano, F, Cl, Br, I, mercapto, nitro, oxo (=O), etc. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1- Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3) ), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc. The term "alkyl" and its prefix "alkane" are used here to refer to both straight-chain and branched saturated carbon chains. The term "alkane" is used here to refer to a saturated divalent hydrocarbon group obtained by eliminating two hydrogen atoms from a straight-chain or branched saturated hydrocarbon; examples include, but are not limited to, methylene, methine, methinepropyl, etc.

[0088] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, or tricyclic system containing 3-12 ring carbon atoms, with one or more linkages to the remainder of the molecule. In some embodiments, the cycloalkyl group is a ring system containing 3-10 ring carbon atoms; in other embodiments, it is a ring system containing 3-8 ring carbon atoms; in still other embodiments, it is a ring system containing 3-6 ring carbon atoms; and in yet another embodiment, it is a ring system containing 5-6 ring carbon atoms. The cycloalkyl group may be independently unsubstituted or substituted by one or more substituents described in this invention.

[0089] The term "aryl" can be used alone or as a part of "aralkyl," "aralkylalkoxy," or "aryloxyalkyl," referring to a monocyclic, bicyclic, or tricyclic carbocyclic system containing 6-14 membered rings, wherein at least one ring system is aromatic, and each ring system contains 3-7 membered rings with one or more attachment sites connected to the rest of the molecule. The term "aryl" can be used interchangeably with the term "aromatic ring," as aromatic rings can include phenyl, naphthyl, and anthracene. Furthermore, the aryl group can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyl-substituted alkoxy, etc.

[0090] The term "heteroaryl" can be used alone or as a part of "heteroarylalkyl" or "heteroarylalkoxy" to refer to monocyclic, bicyclic, and tricyclic systems containing 5-14 membered rings, 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 this invention, wherein each ring system contains 3-7 membered rings and has one or more attachment sites connected to the remainder of the molecule. The term "heteroaryl" can be used interchangeably with the terms "aromatic heterocyclic" or "heteroaromatic compound". Furthermore, the heteroaryl group can be substituted or unsubstituted, wherein the substituent can be, but is not limited to, deuterium, hydroxyl, amino, halogen, cyano, aryl, heteroaryl, alkoxy, alkylamino, alkyl, alkenyl, alkynyl, heterocyclic, mercapto, nitro, aryloxy, hydroxy-substituted alkoxy, hydroxy-substituted alkyl-C(=O)-, alkyl-C(=O)-, alkyl-S(=O)2-, hydroxy-substituted alkyl-S(=O)-, hydroxy-substituted alkyl-S(=O)2-, carboxyl-substituted alkoxy, etc.

[0091] Other embodiments include, but are not limited to, the following monocyclic aromatic rings: 2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 4-methylisoxazol-5-yl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, pyrimidin-5-yl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thiophenyl, 3-thiophenyl, pyrazolyl (e.g., 2-pyrazolyl) ), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiodiazolyl, 1,3,4-thiodiazolyl, 1,2,5-thiodiazolyl, 1,3,4-thiadiazol-2-yl, pyrazinyl, pyrazin-2-yl, 1,3,5-triazinyl, benzo[d]thiazolyl Azol-2-yl, imidazo[1,5-a]pyridin-6-yl; also includes, but is by no means limited to, the following bicyclic compounds: benzimidazolyl, benzofuranyl, benzothiophenyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl) and isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl).

[0092] The term "halogen" refers to F, Cl, Br, and I.

[0093] Additionally, it should be noted that, unless otherwise explicitly stated, the descriptive phrases "each...independently is" and "...and each...independently is" used throughout this document are interchangeable and should be interpreted broadly. They can mean either that the specific options expressed by the same symbol in different groups do not affect each other, or that the specific options expressed by the same symbol in the same group do not affect each other, such as structure... and structure R in both 6 The specific options do not affect each other, and multiple Rs appear in the same structure. 6 multiple R 6 The specific options between them do not affect each other, that is, R 6 The specific options can be the same or different.

[0094] The definitions and conventions of stereochemistry used in this invention are generally referenced in the following literature: 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 this invention may contain asymmetric or chiral centers, and therefore exist as different stereoisomers. All stereoisomers of the compounds of this invention, including, but not limited to, diastereomers, enantiomers, transisomers, and mixtures thereof, such as racemic mixtures, constitute a part of this invention. Many organic compounds exist in optically active forms, i.e., they are capable of rotating the plane of plane-polarized light. In describing optically active compounds, the prefixes D, L, or R, S are used to indicate the absolute configuration of the chiral center of the molecule. The prefixes d, l, or (+), (-) are used to name the symbols for the plane polarization rotation of compounds. (-) or l indicates that the compound is levorotatory, while the prefix (+) or d indicates that the compound is dextrorotatory. These stereoisomers have the same chemical structure, but their stereostructures are different. Specific stereoisomers can be enantiomers, and mixtures of isomers are usually called enantiomeric mixtures. A 50:50 enantiomeric mixture is called a racemic mixture or racemate, which may result in a lack of stereoselectivity or stereodirection during chemical reactions. The terms "racemic mixture" and "racemate" refer to a mixture of two equimolar enantiomers that lack optical activity.

[0095] The terms "tautomer" or "tautomerism form" refer to isomers of different energies that can interconvert through a low energy barrier. For example, proton tautomers (i.e., proton-transfer tautomers) include interconversions via proton transfer, such as isomerization between keto-enol and imine-enamine forms. Valence tautomers include interconversions involving the recombination of bonding electrons.

[0096] As used in this invention, "pharmaceutically acceptable salt" refers to the organic and inorganic salts of the compounds of this invention. Pharmaceutically acceptable salts are well-known in the field, as described in SMBerge et al., J. Pharmaceutical Sciences, 66, 1-19, 1977. Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts formed by reaction with amino groups, such as hydrochlorides, hydrobromic acids, phosphates, sulfates, and perchlorates, and organic acid salts, such as acetates, oxalates, maleates, tartrates, citrates, succinates, and malonates, or salts obtained by other methods described in the literature, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, glucono-heptahydrate, glyceryl phosphate, gluconate, hemisulfate, heptahydrate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pyruvate, pectinate, persulfate, 3-phenylpropionate, picrate, pentanoate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Salts obtained by means of appropriate bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4 Salts of alkyl groups (4). This invention also envisions quaternary ammonium salts formed from any compound containing an N group. Water-soluble or oil-soluble or dispersed products can be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium / quaternary ammonium salts and amine cations resistant to the formation of equilibrium ions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C... 1-8 Sulfonates and aromatic sulfonates.

[0097] In this invention, "solvent" refers to an association formed by one or more solvent molecules and the compound of this invention. Solvents forming solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association formed by solvent molecules that are water.

[0098] The following abbreviations are used throughout this invention:

[0099] DOTA represents 1,4,7,10-tetraazacyclododecane-N,N`,N``,N```,-tetraacetic acid; NOOTA represents 1,4,7-triazacyclononane-1,4,7-triacetic acid; NODAGA represents 2-(4,7-bis(carboxymethyl)-1,4,7-triazononane-1-yl)glutaric acid; DOTAGA represents 2-(4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl)glutaric acid; TRAP represents 1,4,7-triazacyclononanephosphonic acid; NOPO represents 1,4,7-triazacyclononane-1-[methyl(2-carboxyethyl)phosphonic acid]-4,7-bis[methyl(2-carboxymethyl)phosphonic acid]; DFO represents N'-{5-[acetyl(hydroxy)amino]pentyl}-N-[5- ({4-[5-aminopentyl)(hydroxy)amino]-4-oxobutyryl}amino)pentyl]-N-hydroxysuccinamide, DTPA represents diethylenetriaminepentaacetic acid, CHX-DTPA represents trans-cyclohexyl-diethylenetriaminepentaacetic acid, SCN-Bz-DTPA represents p-isocyanothiobenzyl-DTPA, 1B3M represents 1-(isocyanothiobenzyl)-3-methyl-DTPA; 1B3B represents 1-(isocyanothiobenzyl)-4-methyl-DTPA; MX-DTPA represents 1-(2)-methyl-4-isocyanobenzyl-DTPA; oxy-Do3A represents 2-oxazan-4,7,10-triazacyclododecane-4,7,10-triacetic acid; HYNIC represents 6-hydrazylnicotinic acid succinimide hydrochloride; MAG3 represents mercaptoacetyl triglycine.

[0100] The structure of the sulfonated-Cy7 fluorescent group is as follows:

[0101] Attached Figure Description

[0102] The above and / or additional aspects and advantages of the present invention will become apparent and readily understood from the description of the embodiments taken in conjunction with the following drawings, in which:

[0103] Figure 1 This is the LC-MS spectrum of the NYM005 molecule according to an embodiment of the present invention;

[0104] Figure 2 This is an HPLC spectrum of the NYM005 molecule according to an embodiment of the present invention;

[0105] Figure 3 According to an embodiment of the present invention 68 Image of purity analysis results of Ga-NYM005 molecules by radiometric thin-layer chromatography;

[0106] Figure 4These are pathological slide images according to embodiments of the present invention, wherein the upper image is an HE pathological slide lesion image, and the lower image is a slide imaging image;

[0107] Figure 5 According to an embodiment of the present invention 68 PET / CT imaging results of Ga-NYM005 drug in 786-O tumor-bearing mouse model, where the arrows indicate the tumor sites;

[0108] Figure 6 According to an embodiment of the present invention 68 PET / CT imaging results of Ga-NYM005 drug in OS-RC-2 tumor-bearing mouse model, where the arrows indicate the tumor sites;

[0109] Figure 7 According to an embodiment of the present invention 68 PET / CT scan results of Ga-NYM005 drug in 786-O tumor-bearing mouse model, showing tissue distribution and targeted imaging, with arrows indicating tumor sites;

[0110] Figure 8 According to an embodiment of the present invention 68 The competitive inhibition results of Ga-NYM005 in the 786-O tumor-bearing mouse model are shown in the figure, where the arrows indicate the tumor sites.

[0111] Figure 9 This is a blood drug concentration-time graph in mice according to an embodiment of the present invention;

[0112] Figure 10 According to an embodiment of the present invention 68 PET / CT imaging results of Ga-NYM005 in HT29, PC3, and U87 tumor-bearing mouse models, where the arrows indicate the tumor sites;

[0113] Figure 11 According to an embodiment of the present invention 68 PET / CT imaging results of Ga-NYM005 on the HCT116 tumor-bearing mouse model, where the arrows indicate the tumor sites;

[0114] Figure 12 This is a graph showing the weight change of a mouse according to an embodiment of the present invention;

[0115] Figure 13 According to an embodiment of the present invention 68 Ga-NYM005 fluorescent molecule research and clinical PET / CT imaging results;

[0116] Figure 14 This is the LC-MS spectrum of the NYM034 molecule according to an embodiment of the present invention;

[0117] Figure 15 This is an HPLC spectrum of the NYM034 molecule according to an embodiment of the present invention;

[0118] Figure 16 According to an embodiment of the present invention 68 Figure 1. Radiometric thin-layer chromatography purity analysis results of Ga-NYM034 molecules;

[0119] Figure 17 According to an embodiment of the present invention 68 PET / CT imaging results of Ga-NYM034 in 786-O and OS-RC-2 tumor-bearing mouse models, where the arrows indicate the tumor sites;

[0120] Figure 18 This is the LC-MS spectrum of the NYM035 molecule according to an embodiment of the present invention;

[0121] Figure 19 This is an HPLC spectrum of the NYM035 molecule according to an embodiment of the present invention;

[0122] Figure 20 According to an embodiment of the present invention 68 Figure 1. Results of purity analysis of Ga-NYM035 molecules by radiometric thin-layer chromatography.

[0123] Figure 21 According to an embodiment of the present invention 68 PET / CT imaging results of Ga-NYM035 in 786-O and OS-RC-2 tumor-bearing mouse models, with the arrows indicating the tumor sites. Detailed Implementation

[0124] The present invention will now be described with reference to specific embodiments. It should be noted that these embodiments are merely descriptive and do not limit the present invention in any way.

[0125] Example 1

[0126]

[0127] Synthesis route:

[0128]

[0129] First, acetazolamide (1') is hydrolyzed under acidic conditions to obtain compound (2'). Compound (2') undergoes an amide condensation reaction with an aliphatic carboxylic acid (3') to generate compound (4'). Subsequently, the R3 functional group in the structure of compound (4') undergoes an amide condensation or [3+2] cycloaddition reaction with the R4 functional group in the structure of compound (5) to generate compound (6'), where R3 is a terminal acetylene or carboxyl group, and R4 is an azide or amino group. Compound (6') is deprotected under suitable strongly acidic conditions to obtain compound (7'). Finally, compound (7') undergoes a condensation reaction with a carboxyl group or an active ester of a chelating group or fluorescent group to obtain the target compound (II).

[0130] Example 2: Preparation process of NYM005 molecule

[0131]

[0132] Its LC-MS spectrum is shown below. Figure 1 HPLC chromatograms are shown below. Figure 2 .

[0133] Synthesis route:

[0134] Step 1:

[0135]

[0136] Compound (1b) (5.00 g, 22.5 mmol, 1.00 eq) was added to 50 mL of EtOH solvent, and hydrochloric acid (12.0 M, 7.50 mL, 4.00 eq) was added at 25 °C. The mixture was refluxed at 78 °C for 16 hours. TLC (volume ratio: dichloromethane:methanol = 5:1) showed the formation of a new compound. The reaction solution was cooled to 25 °C, and the reaction mixture was poured into water (30.0 mL). Saturated sodium bicarbonate was added to adjust the pH to 7, and the mixture was extracted three times with 30 mL of ethyl acetate each time. The extracted organic layer was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the residue. The residue was a yellow oily substance (2b) (12.0 g, 35.0 mmol).

[0137] Step Two:

[0138]

[0139] Compound (a) (2.00 g, 17.8 mmol, 1.94 mL, 1.00 mL) was added to DCM (20.0 mL) solvent. DMF (65.1 mg, 891 μmol, 68.6 μL, 0.05 eq) was added to this solution. The solution was cooled to 0 °C, and oxaloyl dichloride (2.15 g, 16.9 mmol, 1.48 mL, 0.95 eq) was added dropwise. The mixture was stirred at 20 °C for 3 h. The reaction mixture was concentrated under pressure to give hex-5-ynoyl chloride (2.03 g, 15.5 mmol) as a yellow oil.

[0140] Compound (2b) (2.70 g, 14.9 mmol, 1.00 eq) and pyridine (2.37 g, 29.9 mmol, 2.42 mL, 2.00 eq) were added to DMF solvent (28.0 mL) to form a mixture, which was then cooled to 0 °C. Hex-5-ynoyl chloride (1.96 g, 14.9 mmol, 1.00 eq) was dissolved in DCM solvent (20.0 mL) and added dropwise to the mixture at 0 °C. The mixture was stirred at 25 °C for 12 hours. The resulting mixture was concentrated under reduced pressure to remove the solvent and obtain a residue. The residue was purified by preparative-high performance liquid chromatography to give a white solid compound (3b) (2.75 g, 9.95 mmol).

[0141] Step 3:

[0142] Peptide synthesis: Peptide synthesis was performed using the Fmoc synthesis method.

[0143]

[0144] 1. Resin Preparation: 20.0 mL of DCM solution containing Fmoc-Asp-OAll (1.00 mmol, 1.00 eq) and DIEA (4.00 mmol, 4.00 eq) was added to 2-CTC resin (1.00 mmol, 1.00 eq). The mixture was purged with nitrogen at 20 °C and stirred for 2 hours. Then, MeOH (1.00 mL) was added and stirring continued for 30.0 min. Subsequently, the resin was washed five times with DMF (20.0 mL * 5), each time using 20.0 mL of DMF.

[0145] 2. Deprotection: Add a DMF solution containing 20% ​​piperidine (20.0 mL) to the resin, stir for 30.0 min under nitrogen purging, and wash the filter resin with DMF (20.0 mL * 5) five times, using 20.0 mL of DMF each time.

[0146] 3. Coupling: Add 5-azidopentanoic acid (3.00 mmol, 3.00 eq) to DMF (10.0 mL) solvent, and add HATU (3.00 mmol, 3.00 eq) and DIEA (6.00 mmol, 6.00 eq). Add the mixture to the resin and stir for 30.0 min at 20 °C under nitrogen purging. Wash the resin with DMF (20.0 mL * 5) five times, using 20.0 mL of DMF each time.

[0147] 4. Add compound (3b) (3.00 mmol, 3.00 eq), CuI (0.50 mmol, 0.50 eq), and DIEA (4.00 mmol, 4.00 eq) to DMF (20.0 mL) solvent. Purge with nitrogen and stir at 20 °C for 16 hours. Then wash the resin with DMF (20.0 mL * 5) five times, using 20.0 mL of DMF each time.

[0148] 5. Deprotection: Add PhSiH3 (10.0 mmol, 10.0 eq) and Pd(PPh3)4 (0.10 mmol, 0.10 eq) to the resin, stir for 15.0 min*3 under nitrogen purging, stirring three times, 15 min each time. Wash the filter resin with DMF (20.0 mL*5) five times, using 20.0 mL of DMF each time.

[0149] 6. Repeat steps 2-3 above to couple the amino acids in Table 1:

[0150] Table 1

[0151] N-Fmoc-1,4-Diaminobutane·HCl(3.00eq) HOAT (3.00eq), DIC (3.00eq) NOTA-bis(tBu)ester(1.50eq) HOAT (1.50 eq), DIC (1.50 eq)

[0152] 7. Wash the resin with DMF (20.0 mL * 5) five times, each time using 20.0 mL of DMF, and filter to obtain polypeptide (4b).

[0153] 8. Peptide cleavage and purification:

[0154] The resin was washed three times with 20.0 mL of MeOH each time, and dried under vacuum to obtain 2.0 g of peptide resin (4b). The peptide with the side-chain protecting group was added to a flask, and 20 mL of lysis buffer (92.5% TFA / 2.5% TIS / 2.5% H2O / 2.5% MPR) was added. The mixture was stirred at 20 °C for 2 hours to remove the protection. The peptide was precipitated with 100 mL of tert-butyl methyl ether and centrifuged (3.00 min, 3000 rpm). The peptide precipitate was then washed twice with 100 mL of tert-butyl methyl ether. The obtained product was dried under vacuum for 2 hours to obtain 0.821 g of crude product.

[0155] The target product NYM005 (105 mg, 101 μmol, purity 96.30%) was purified by preparative high performance liquid chromatography (TFA conditions: A: 0.075% TFA in H2O solution, B: ACN) to obtain a white solid.

[0156] Example 3 68 Preparation process of Ga-NYM005

[0157] The synthesized NYM005 precursor was reacted with the radioactive nuclide gallium [ 68 Ga] chelation reaction further yields results that can be used for clinical PET / CT tracing. 68 Ga-NYM005 tracer has a mature labeling technology, and the chemical purity of the labeled product radioactive compound can usually reach 99%.

[0158] The labeling process is shown below. The entire labeling process can be completed within 20 minutes, and the yield of radioactive compounds can reach 70%.

[0159]

[0160] This embodiment 68 The specific steps for marking NYM005 with Ga are as follows: 68 Ga nuclide was obtained by rinsing the germanium-gallium generator with 0.05M hydrochloric acid solution. 1 mL of this solution was then used. 68 A Ga nuclide (20 mCi) solution was added to the reaction flask, followed by 1 mL of 0.3 mol / L acetic acid / sodium acetate buffer solution. 68 The volume ratio of Ga nuclide to buffer solution was 1:1, and the pH was adjusted to 4.0. An appropriate amount of the NYM005 precursor compound was added to sterile water for injection to prepare a 1 mg / mL precursor solution. Then, 45 nmol (40 μg) was added to the reaction flask, and the reaction was carried out at 105°C for 6 min. After the reaction was completed, the mixture was cooled for 1 min. Using a 10 mL sterile syringe, 5 mL of sterile water for injection was added to the reaction flask to dilute the reaction solution and lower its temperature. All the liquid in the reaction flask was then drawn into the syringe. A pre-activated Sep-Pak C-18 column was attached to the syringe outlet, and the reaction dilution was pushed through the Sep-Pak C-18 column to obtain the target product. 68 Ga-NYM005 was adsorbed onto a C-18 column, and then the C-18 column was rinsed with 1 mL of 70% medical-grade anhydrous ethanol solution. The eluent was filtered through a 0.22 μm sterile filter membrane and flowed into a sterile vacuum bottle. 4 mL of physiological saline solution was then added to obtain the final product. 68 Ga-NYM005 sterile injection solution.

[0161] Quality control of the above products was performed using radiometric thin-layer chromatography (TLC). The support was glass fiber paper, and the developing solvent was 0.5 M citric acid / sodium citrate buffer (pH=5). A glass fiber paper was used, and the sample was gently spotted onto the paper 1.5 cm from the bottom using a pipette. The sample was then placed in a test tube containing 500 μL of 0.5 M citric acid / sodium citrate buffer (pH=5). The mixture was developed to a depth of 2.5 cm from the top of the chromatographic paper, removed, and allowed to dry. Radio-TLC was then used for analysis. Under the 0.5 M citric acid / sodium citrate buffer (pH=5) system, the Rf value of the product was between 0.3 and 0.6. Figure 3 As shown, 68 The purity analysis results of Ga-NYM005 molecular radioactive thin-layer chromatography showed that the chemical purity of the radioactive compound was 100%.

[0162] Example 4 68 Ga-NYM005 autoradiography experiment

[0163] Paraffin sections of pancreatic cancer and clear cell renal cell carcinoma were baked, dewaxed, and hydrated to prepare the required concentrations. 68 Ga-NYM005 drug, 0.3-0.4 ml of radiopharmaceutical per slice. 68 Incubation with Ga-NYM005 at room temperature for 35 minutes, followed by elution, drying, and then phosphorus screen imaging. The imaging results of pancreatic cancer sections are shown below. Figure 4 As shown, there is no obvious radioactive concentration, while the imaging results of the renal cell carcinoma section show high radioactive concentration, which is consistent with the location of the lesion in the HE pathological section.

[0164] Example 5 68 Imaging results of Ga-NYM005 in a 786-O tumor-bearing mouse model

[0165] The 786-O experimental animal model was provided by Hengjia Biotechnology (Suzhou) Co., Ltd. It is a subcutaneous heterotopic xenograft model of 786-O tumors established in BALB / c nude mice. This model is a mouse model constructed from human renal clear cell adenocarcinoma cells. Two animals were randomly selected from this model, and each was given the above-mentioned treatment. 68 Administer 100 μCi of Ga-NYM005 drug. Before scanning, animals were pre-anesthetized with an appropriate concentration of isoflurane / oxygen gas mixture. The animals were then placed on a Siemens Inveon small animal PET / CT scanning bed and continuously anesthetized with isoflurane / oxygen gas mixture. A 10-minute PET scan was performed 1 hour after drug administration. The scanned images were obtained after automatic data reconstruction by the device software and analyzed using PMOD software. Figure 5 As shown (the arrow indicates the tumor location), analysis of the scan data... 68The high enrichment of Ga-NYM005 at the tumor site indicates that the drug has good tumor targeting properties, and the drug that is not taken up by the tumor is rapidly excreted through the kidneys and bladder.

[0166] Example 6 68 Imaging results of Ga-NYM005 in the OS-RC-2 tumor-bearing mouse model

[0167] The OS-RC-2 experimental animal model was provided by Hengjia Biotechnology (Suzhou) Co., Ltd. It is a subcutaneous heterotopic tumor xenograft model of OS-RC-2 tumor established in BALB / c nude mice, which is a mouse model constructed from human renal cell carcinoma cells. Two of these animal models were selected, and each was given the above-mentioned treatment. 68 Ga-NYM005 drug 100 μCi was administered. Before scanning, animals were pre-anesthetized with an appropriate concentration of isoflurane / air gas mixture. They were then placed in a MicroPET / CT imaging chamber (SNPC-303 Super Nova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.) and anesthesia was maintained using isoflurane / air gas mixture. MicroPET / CT scans were performed 1 hour after drug administration. Images were reconstructed using the equipment software and analyzed using PMOD software. Results are as follows: Figure 6 As shown (the arrow indicates the tumor uptake site), 68 The high enrichment of Ga-NYM005 at the tumor site indicates that the drug has good tumor targeting properties, and the drug that is not taken up by the tumor is rapidly excreted through the kidneys and bladder.

[0168] Example 7 68 PET / CT scan tissue distribution and targeting of Ga-NYM005 drug in 786-O tumor-bearing mouse model

[0169] The 786-O experimental animal model was provided by Shanghai Biaodu Biotechnology Co., Ltd., and is a subcutaneous heterotopic xenograft model of 786-O tumors established in NOD-SCID mice. This model is a mouse model constructed from human renal clear cell adenocarcinoma cells. Two of these animal models were selected, and each was given the above-mentioned treatment. 68 Ga-NYM005 drug 100 μCi was administered. Before scanning, animals were pre-anesthetized with an appropriate concentration of isoflurane / air gas mixture. They were then placed in a MicroPET / CT imaging chamber (SNPC-303 SuperNova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.) and anesthesia was maintained using isoflurane / air gas mixture. MicroPET / CT scans were performed 1 hour after drug administration. Images were reconstructed using the equipment software and analyzed using PMOD software. Results are as follows: Figure 7 As shown (the arrow indicates the tumor location), 68The biodistribution of Ga-NYM005 in 786-O tumor model mice showed that it was mainly excreted through the kidney and bladder, with high radioactivity concentration in tumor tissue and low uptake in other tissues.

[0170] Example 8 68 Competitive inhibition experiment of Ga-NYM005 drug in 786-0 mouse model

[0171] The 786-O animal model, provided by Shanghai Biaodu Biotechnology Co., Ltd., is a subcutaneous heterotopic xenograft model of 786-O tumors established in NOD-SCID mice. This model is a mouse model constructed from human renal clear cell adenocarcinoma cells. Two mice were randomly selected from this animal model, and the mice were injected intravenously with the cold drug NYM0005 at a dose equal to the dosage of the heated drug. 68 The dosage of Ga-NYM0005 was 40 times that of the original drug, and the administration sequence was to administer the hot drug 30 minutes after administering the cold drug. 68 For Ga-NYM0005, after pre-anesthesia with an appropriate concentration of isoflurane / air mixture gas, the animal was placed in a MicroPET / CT imaging chamber (SNPC-303 Super Nova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.) and anesthesia was maintained using isoflurane / air mixture gas. MicroPET / CT scanning was performed 1 hour after administration of the hyperthermic drug. The scanned images were reconstructed using the equipment software and analyzed using PMOD software. Results are as follows: Figure 8 As shown (arrow points to the tumor), adding cryotherapy can significantly block the tumor's response to... 68 Ga-NYM005 uptake, thus confirming the tumor's effect on... 68 The uptake of Ga-NYM005 is a specific targeted uptake.

[0172] Example 9: Tissue distribution experiment and blood pharmacokinetics experiment in ICR mice

[0173] Female ICR mice aged 4-6 weeks were purchased from Hengjia Biotechnology (Suzhou) Co., Ltd. Four ICR mice were randomly selected from each mouse and administered the above treatment. 68 50 μCi of Ga-NYM005 was administered via submandibular blood sampling at 5 min, 15 min, 30 min, 45 min, 60 min, 2 h, 3 h, and 4 h post-administration to measure gamma counts. Blood drug concentrations at different time points were calculated, and pharmacokinetic parameters for a non-compartmental model were calculated using the pharmacokinetic counting software DAS (as shown in Table 2). Results are as follows: Figure 9 As shown, the pharmacokinetic calculation results are: elimination half-life t1 / 2z = 5.81 h, peak time Tmax approximately 0.0833 h, and peak concentration Cmax approximately 225.6 ug / L, indicating good pharmacokinetic activity.

[0174] Table 2. Pharmacokinetic parameters of the non-compartmental model calculated using the pharmacokinetic counting software DAS.

[0175] 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 returns to its final point 124 Cz (Tail Point Regression Value) 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

[0176] Example 10 68 Experiments on tissue distribution and targeting of Ga-NYM005 in HT29, PC3, and U87 model PET scans.

[0177] The HT29, PC3, and U87 experimental animal models were provided by Hengjia Biotechnology (Suzhou) Co., Ltd. These were subcutaneous heterotopic tumor models of HT29, PC3, and U87 tumors established in BALB / c nude mice, representing human colon cancer cells, human prostate cancer cells, and human glioma, respectively. One animal from each of these models was randomly selected, and each animal was administered the aforementioned treatments. 68 80 μCi of Ga-NYM005 drug was administered. Animals were pre-anesthetized with an appropriate concentration of isoflurane / oxygen gas before scanning. They were then placed in the Super Nova small animal PET / CT scanning chamber of Pingsheng Medical and continuously anesthetized with isoflurane / oxygen gas. MicroPET / CT scanning was performed 1 hour after drug administration. Images were obtained after reconstruction using the equipment software and analyzed using PMOD software. Results are as follows: Figure 10 As shown (the arrow indicates the tumor location), 68 Ga-NYM005 showed no significant high uptake at the tumor site, indicating that... 68 Ga-NYM005 has no targeting properties in tumors such as HT29, PC3, and U87.

[0178] Example 11 68 Experiments on tissue distribution and targeting of Ga-NYM005 in HCT116 model PET / CT scans

[0179] The experimental animal model of HCT116 was provided by Hengjia Biotechnology (Suzhou) Co., Ltd. It is a subcutaneous heterotopic xenograft model of HCT116 tumor established in BALB / c nude mice, which is a mouse model constructed from human colon cancer cells. Two of these animal models were selected, and each was given the above-mentioned treatment. 68 Ga-NYM005 drug 100 μCi was administered. Before scanning, animals were pre-anesthetized with an appropriate concentration of isoflurane / air gas mixture. They were then placed in a MicroPET / CT imaging chamber (SNPC-303 Super Nova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.) and anesthesia was maintained using isoflurane / air gas mixture. MicroPET / CT scans were performed 1 hour after drug administration. Images were reconstructed using the equipment software and analyzed using PMOD software. Results are as follows: Figure 11As shown (the arrow indicates the tumor location), 68 Ga-NYM005 showed no significant high uptake at the tumor site, indicating that... 68 Ga-NYM005 showed no targeting in HCT116 tumors.

[0180] Example 12 Safety Evaluation Experiment

[0181] In accordance with the hospital's research and clinical ethics requirements for the toxicity evaluation of positron emission tomography tracers, six ICR mice were selected as experimental animals. The supplier was Merrick (Suzhou) Technology Service Co., Ltd., and each animal was given 300 μCi. 68 Ga-NYM005 sterile injection was administered, and patients were observed for 7 consecutive days afterward. Results were as follows: Figure 12 As shown, during the 7-day observation period, none of the mice died or showed any abnormal reactions, and all mice gained weight after the experiment. 68 Ga-NYM005 has good molecular safety and meets the needs of scientific research and clinical drug use.

[0182] Example 13 68 Ga-NYM005 Internal Radiation Dose Estimation

[0183] Three ICR mice were used, and each mouse was given 100 μCi of radiopharmaceutical. 68 After Ga-NYM005, a dynamic 30-minute scan was performed, followed by a 10-minute static scan at 1h, 2h, 3h, and 4h time points. Based on the scan data, tissue distribution data at different time points in normal mice could be obtained. Then, the residence time of each organ in the mouse was calculated using PMOD software, and the residence time of human organs was extrapolated from the residence time of each organ in the mouse. Finally, the radiation dose in the human body was calculated using OLIDA software. The calculation result was that the overall effective dose ED = 0.011mSv / MBq. Based on the clinical drug dosage of 111MBq (3mCi) / person, the total effective radiation dose was 1.221mSv / person, which is much lower than the dose of 10-15mSv of conventional CT chest and abdominal scans and is within the safe range. The radiation dose estimation table is shown in Table 3 below.

[0184] Table 3. Calculation of Intra-organ Irradiation Dose for Clinical Patients in Scientific Research

[0185]

[0186]

[0187] Example 14 68 Ga-NYM005 Imaging Results from Scientific and Clinical Trials

[0188] The patient underwent PEC / CT imaging with 18F-FDG, a commonly used early tumor screening tracer, which revealed a mass in the right kidney, with metastases to both lungs and mediastinal lymph nodes. A subsequent right kidney biopsy revealed clear cell carcinoma, WHO / ISUP nuclear grade 2, Vimentin 9+, PAX-8+, P504S+, and Ki67 10%. After being recommended by the clinician and obtaining informed consent, the patient was administered medication via a dorsal vein in the hand. 68 After administering 5 mCi of Ga-NYM005 sterile injection, wait 1 hour before performing a PET / CT scan. The imaging results are shown below. Figure 13 .

[0189] Analysis of examination results: A soft tissue density mass, approximately 9.2 cm in size, was observed in the right kidney, with abnormally increased radioactive uptake (SUVmax 14.6). A linear lesion with increased radioactive uptake, approximately 4.7 cm long, was observed in the inferior vena cava (SUVmax 12.7). Linear areas of increased radioactive uptake were observed in some pulmonary vessels (SUVmax 3.4). Multiple lymph nodes with increased radioactive uptake were observed in the left retroperitoneum, left hilum, aortopulmonary window, and left supraclavicular region, the largest of which was approximately 1.8 cm (SUVmax 12.5). Multiple soft tissue density nodules were observed in the lungs, the largest of which was approximately 2.5 cm, with increased radioactive uptake (SUVmax 11.6). A lesion with increased radioactive uptake, approximately 1.4 cm long, was observed in the left femoral head (SUVmax 11.1).

[0190] Clinical diagnosis: Right kidney 68 Lesions with high Ga-NYM005 expression may be consistent with clear cell renal cell carcinoma, accompanied by multiple lymph node metastases in the left retroperitoneum, left hilum, aortopulmonary window, and left supraclavicular fossa, multiple intrapulmonary metastases, left femoral head metastases, and tumor thrombus formation in the inferior vena cava and pulmonary artery.

[0191] Through this clinical validation 68 In clinical applications of renal cell carcinoma diagnosis, Ga-NYM005 molecules can detect more tumor metastases than the currently commonly used 18F-FDG tracer, and therefore have greater clinical application value.

[0192] Example 15: Preparation process of NYM034 molecule

[0193]

[0194] Its LC-MS spectrum is shown below. Figure 14 HPLC chromatograms are shown below. Figure 15 .

[0195] Synthesis route:

[0196]

[0197] Peptide synthesis: Peptide synthesis was performed using the Fmoc synthesis method.

[0198] 1. Resin preparation: 10.0 mL of DCM solution containing Fmoc-Asp-Alloc (500 μmol, 1.00 eq) and DIEA (2.00 mmol, 4.00 eq) was added to 2-CTC resin (500 μmol, 1.00 eq). The mixture was purged with nitrogen at 20 °C and stirred for 2 hours. Then, MeOH (500 μL) was added and stirring was continued for 30.0 min. Subsequently, the resin was washed with DMF (20.0 mL * 5) five times, each time using 20.0 mL of DMF.

[0199] 2. Deprotection: Add a DMF solution containing 20% ​​piperidine (20.0 mL) to the resin, stir for 30.0 min under nitrogen purging, and wash the filter resin with DMF (20.0 mL * 5) five times, using 20.0 mL of DMF each time.

[0200] 3. Coupling: Add 5-azidopentanoic acid (1.50 mmol, 3.00 eq) to DMF (20.0 mL) solvent, and add HATU (1.50 mmol, 3.00 eq) and DIEA (3.00 mmol, 6.00 eq). Add the mixture to the resin and stir for 30.0 min at 20 °C under nitrogen purging. Wash the resin with DMF (20.0 mL * 5) five times, using 20.0 mL of DMF each time.

[0201] 4. Repeat steps 2 and 3 above, sequentially coupling the amino acids in Table 4:

[0202] Table 4

[0203] Compound 3b (1.50 eq) CuI (0.50 eq), DIEA (2.00 eq) N-Fmoc-1,4-diaminobutane HCL(3.00eq) HOAt(3.00eq), DIC(3.00eq) <![CDATA[DOTA-(COOt-Bu)3(1.50eq)]]> HOAt(1.50eq), DIC(1.50eq)

[0204] 5. Wash the resin with DMF (20.0 mL * 5) five times, each time using 20.0 mL of DMF, and filter to obtain polypeptide resin (5b).

[0205] 6. Peptide cleavage and purification:

[0206] The resin from the previous step was washed three times with 20.0 mL of MeOH each time, and then dried under vacuum to obtain the polypeptide resin (5b).

[0207] Add the peptide with the side-chain protecting group to a flask and add 20 mL of lysis buffer (92.5% TFA / 2.5% TIS / 2.5% H2O / 2.5% MPR). Stir at 20 °C for 2 hours to deprotect the peptide. Precipitate the peptide with tert-butyl methyl ether (50.0 mL) and centrifuge (3.00 min, 3000 rpm). Wash the precipitate twice with tert-butyl methyl ether (50.0 mL).

[0208] The crude peptide was vacuum dried for 2 hours to obtain 400 mg of crude product.

[0209] Purification was performed using preparative high performance liquid chromatography (TFA conditions: A: 0.075% TFA in H2O solution, B: ACN) to obtain the target product NYM034 (62.0 mg, 55.3 μmol, yield 11.1%, purity 98.45%, TFA), a white solid.

[0210] Example 16 68 Preparation process of Ga-NYM034 molecules

[0211] The synthesized NYM034 precursor was reacted with the radioactive nuclide gallium [ 68 Ga] chelation reaction further yields results that can be used for clinical PET / CT tracing. 68 Ga-NYM034 tracer has a mature labeling technology, and the labeled products typically have a radioactive compound chemical purity of up to 99%.

[0212] The labeling process is shown below. The entire labeling process can be completed within 20 minutes, and the yield of radioactive compounds can reach 70%.

[0213]

[0214] 68 Ga nuclide was obtained by rinsing the germanium-gallium generator with 0.05M hydrochloric acid solution. 1 mL of this solution was then used. 68 A Ga nuclide (20 mCi) solution was added to the reaction flask, followed by 1 mL of 0.3 mol / L acetic acid / sodium acetate buffer solution. 68The volume ratio of Ga nuclide to buffer solution was 1:1, and the pH was adjusted to 4.0. An appropriate amount of the NYM034 precursor compound was added to sterile water for injection to prepare a 1 mg / mL precursor solution. Then, 45 nmol (44.5 μg) was added to the reaction flask, and the reaction was carried out at 105°C for 6 min. After the reaction was completed, the mixture was cooled for 1 min. Using a 10 mL sterile syringe, 5 mL of sterile water for injection was added to the reaction flask to dilute the reaction solution and lower its temperature. All the liquid in the reaction flask was then drawn into the syringe. A pre-activated Sep-Pak C-18 column was attached to the syringe outlet, and the reaction dilution was pushed through the Sep-Pak C-18 column to obtain the target product. 68 Ga-NYM034 was adsorbed onto a C-18 column, and then the C-18 column was rinsed with 1 mL of 70% medical-grade anhydrous ethanol solution. The eluent was filtered through a 0.22 μm sterile filter membrane and flowed into a sterile vacuum bottle. 4 mL of physiological saline solution was then added to obtain the final product. 68 Ga-NYM034 sterile injection solution.

[0215] Quality control of the above products was performed using radiometric thin-layer chromatography (TLC). The support was glass fiber paper, and the developing solvent was 0.5 M citric acid / sodium citrate buffer (pH=5). A glass fiber paper was used, and the sample was gently spotted onto the paper 1.5 cm from the bottom using a pipette. The sample was then placed in a test tube containing 500 μL of 0.5 M citric acid / sodium citrate buffer (pH=5). The mixture was developed to a depth of 2.5 cm from the top of the chromatographic paper, removed, and allowed to dry. Radio-TLC was then used for analysis. Under the 0.5 M citric acid / sodium citrate buffer (pH=5) system, the Rf value of the product was between 0.3 and 0.6. Figure 16 As shown, 68 The purity analysis results of Ga-NYM034 molecular radioactive thin-layer chromatography showed that the chemical purity of the radioactive compound was 100%.

[0216] Example 17 68 Experiments on tissue distribution and targeting of Ga-NYM034 786-O and OS-RC-2 model PET scans

[0217] The 786-O animal model, provided by Hengjia Biotechnology (Suzhou) Co., Ltd., is a subcutaneous heterotopic xenograft model of 786-O tumors established in BALB / c nude mice. This model is a mouse model constructed from human renal clear cell adenocarcinoma cells. The OS-RC-2 animal model, also provided by Hengjia Biotechnology (Suzhou) Co., Ltd., is a subcutaneous heterotopic xenograft model of OS-RC-2 tumors established in BALB / c nude mice. This model is a mouse model constructed from human renal cancer cells. One animal from each of the two models was selected, and each animal was administered the above-mentioned treatments. 68Ga-NYM034 drug 100 μCi was administered. Before scanning, animals were pre-anesthetized with an appropriate concentration of isoflurane / air gas mixture. They were then placed in a MicroPET / CT imaging chamber (SNPC-303 Super Nova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.) and anesthesia was maintained using isoflurane / air gas mixture. MicroPET / CT scans were performed 1 hour after drug administration. Images were reconstructed using the equipment software and analyzed using PMOD software. Results are as follows: Figure 17 As shown (the arrow indicates the tumor location), 68 Ga-NYM034 showed high enrichment in tumor sites in the OS-RC-2 model, but lower uptake in tumors in the 786-O model, indicating that the drug has good tumor targeting in the OS-RC-2 model.

[0218] Example 18: Preparation process of NYM035 molecule

[0219]

[0220] Its LC-MS spectrum is shown below. Figure 18 HPLC chromatograms are shown below. Figure 19 .

[0221] Synthesis route:

[0222] Step 1:

[0223]

[0224] Compound (1a) (3.00 g, 16.7 mmol, 1.00 eq) and pyridine (2.63 g, 33.3 mmol, 2.69 mL, 2.00 eq) were dissolved in 30.0 mL of DMF solvent, and the solution was cooled to 0 °C. Compound (4a) (2.97 g, 16.65 mmol, 1.00 eq) was dissolved in 20.0 mL of DMF solvent, and this solution was added dropwise to the aforementioned solution. The mixture was stirred at 25 °C for 14.0 hours. The reaction solution was concentrated under reduced pressure to remove the solvent. The residue was diluted with 45.0 mL of water and 45.0 mL of saturated NaHCO3, and filtered to obtain compound (2a) (5.00 g, 15.0 mmol) as a white solid.

[0225] Step Two:

[0226]

[0227] Compound (2a) (5.00 g, 15.0 mmol, 1.00 eq) and NaOH (3.45 g, 86.3 mmol, 5.76 eq) were dissolved in 70.0 mL of water, and the mixture was stirred and heated to 60 °C for 1 hour. After cooling, the pH of the reaction solution was adjusted to 4 with 1 mol / L HCl solution. The resulting solid was filtered and washed with water to obtain compound (3a) (2.00 g, 6.22 mmol), a white solid.

[0228] Step 3:

[0229]

[0230] Peptide synthesis: The peptides were synthesized using the Fmoc synthesis method.

[0231] 1. Resin preparation: Fmoc-Asp-Alloc (500 μmol, 1.00 eq) and DIEA (2.00 mmol, 4.00 eq) were dissolved in 10.0 mL of DCM solvent. This solution was added to 2-CTC resin, and the mixture was purged with N2 at 20 °C and stirred for 2 hours. Then, MeOH (500 μL) was added and stirring was continued for 30.0 min. Subsequently, the resin was washed five times with DMF (20.0 mL * 5), each time using 20.0 mL of DMF.

[0232] 2. Deprotection: Add a DMF solution containing 20% ​​piperidine (20.0 mL) to the resin, stir for 30.0 min under N2 purging, and wash the filter resin with DMF (20.0 mL * 5) five times, using 20.0 mL of DMF each time.

[0233] 3. Coupling: Dissolve Fmoc-5-Ava-OH (0.75 mmol, 1.50 eq) in 20.0 mL of DMF solvent. Add HOAt (0.75 mmol, 1.50 eq) and DIC (0.75 mmol, 1.50 eq) to this solution. Add the mixture to the resin and stir for 2 hours at 20 °C under nitrogen purging. Wash the resin with DMF (20.0 mL * 5) five times, using 20.0 mL of DMF each time.

[0234] 4. Repeat steps 2 and 3 above to couple the amino acids in Table 5:

[0235] Table 5

[0236] Compound (3a) (1.50 eq) HOAt(1.50eq) and DIC(1.50eq) Fmoc-Dab.HCl (3.00 eq) HOAt(3.00eq)and DIC(3.00eq) <![CDATA[DOTA-(COOt-Bu)3(1.50eq)]]> HOAt(1.50eq) and DIC(1.50eq)

[0237] 5. Wash the resin with DMF (20.0 mL * 5), filter to obtain polypeptide resin (5a), wash five times, each time using 20.0 mL of DMF.

[0238] 6. Peptide cleavage and purification:

[0239] Wash with MeOH (20.0 mL * 3) three times, each time using 20.0 mL of MeOH, and then vacuum dry to obtain polypeptide resin (5a).

[0240] Add the polypeptide (5a) with the side-chain protecting group to a flask and add 20 mL of lysis buffer (92.5% TFA / 2.5% TIS / 2.5% H2O / 2.5% MPR). Stir at 20 °C for 2 hours to deprotect the polypeptide. Precipitate the polypeptide with tert-butyl methyl ether (50.0 mL) and centrifuge (3.00 min, 3000 rpm). Wash the precipitate twice with tert-butyl methyl ether (50.0 mL).

[0241] The crude peptide was vacuum dried for 2 hours to obtain 400 mg of crude product.

[0242] The target product NYM035 (80.0 mg, 72.2 μmol, yield 14.4%, purity 98.68%) was obtained by preparative-high performance liquid chromatography (TFA conditions: A: 0.075% TFA in H2O solution, B: ACN) purification, and was a white solid.

[0243] Example 19 68 Preparation process of Ga-NYM035 molecules

[0244] The synthesized NYM035 precursor was reacted with the radioactive nuclide gallium [ 68 Ga] chelation reaction further yields results that can be used for clinical PET / CT tracing. 68 Ga-NYM035 tracer has a mature labeling technology, and the chemical purity of the labeled product radioactive compound can usually reach 99%.

[0245] The labeling process is shown below. The entire labeling process can be completed within 20 minutes, and the yield of radioactive compounds can reach 70%.

[0246]

[0247] This embodiment 68 The specific steps for marking NYM035 with Ga are as follows: 68 Ga nuclide was obtained by rinsing the germanium-gallium generator with 0.05M hydrochloric acid solution. 1 mL of this solution was then used. 68 A Ga nuclide (20 mCi) solution was added to the reaction flask, followed by 1 mL of 0.3 mol / L acetic acid / sodium acetate buffer solution. 68The volume ratio of Ga nuclide to buffer solution was 1:1, and the pH was adjusted to 4.0. An appropriate amount of the NYM035 precursor compound was added to sterile water for injection to prepare a 1 mg / mL precursor solution. Then, 45 nmol (44 μg) was added to the reaction flask and reacted at 105 °C for 6 min. After the reaction was complete, the mixture was cooled for 1 min. Using a 10 mL sterile syringe, 5 mL of sterile water for injection was added to the reaction flask to dilute the reaction solution and lower its temperature. All the liquid in the reaction flask was then drawn into the syringe. A pre-activated Sep-Pak C-18 column was attached to the syringe outlet, and the reaction dilution was pushed through the Sep-Pak C-18 column to obtain the target product. 68 Ga-NYM035 was adsorbed onto a C-18 column, and then the C-18 column was rinsed with 1 mL of 70% medical-grade anhydrous ethanol solution. The eluent was filtered through a 0.22 μm sterile filter membrane and flowed into a sterile vacuum bottle. 4 mL of physiological saline solution was then added to obtain the final product. 68 Ga-NYM035 sterile injection solution.

[0248] Quality control of the above products was performed using radiometric thin-layer chromatography (TLC). The support was glass fiber paper, and the developing solvent was 0.5 M citric acid / sodium citrate buffer (pH=5). A glass fiber paper was used, and the sample was gently spotted onto the paper 1.5 cm from the bottom using a pipette. The sample was then placed in a test tube containing 500 μL of 0.5 M citric acid / sodium citrate buffer (pH=5). The mixture was developed to a depth of 2.5 cm from the top of the chromatographic paper, removed, and allowed to dry. Radio-TLC was then used for analysis. Under the 0.5 M citric acid / sodium citrate buffer (pH=5) system, the Rf value of the product was between 0.3 and 0.6. Figure 20 As shown, 68 The purity analysis results of Ga-NYM035 molecular radioactive thin-layer chromatography showed that the chemical purity of the radioactive compound was 100%.

[0249] Example 20 68 PET scan tissue distribution and targeting experiments using Ga-NYM035 786-O and OS-RC-2 models.

[0250] The 786-O animal model, provided by Hengjia Biotechnology (Suzhou) Co., Ltd., is a subcutaneous heterotopic xenograft model of 786-O tumors established in BALB / c nude mice. This model is a mouse model constructed from human renal clear cell adenocarcinoma cells. The OS-RC-2 animal model, also provided by Hengjia Biotechnology (Suzhou) Co., Ltd., is a subcutaneous heterotopic xenograft model of OS-RC-2 tumors established in BALB / c nude mice. This model is a mouse model constructed from human renal cancer cells. One animal from each of the two models was selected, and each animal was administered the above-mentioned treatments. 68Ga-NYM035 drug 100 μCi was administered. Before scanning, animals were pre-anesthetized with an appropriate concentration of isoflurane / air gas mixture. They were then placed in a MicroPET / CT imaging chamber (SNPC-303 Super Nova, Ping Sheng Medical Technology (Kunshan) Co., Ltd.) and anesthesia was maintained using isoflurane / air gas mixture. MicroPET / CT scans were performed 1 hour after drug administration. Images were reconstructed using the equipment software and analyzed using PMOD software. Results are as follows: Figure 21 As shown (the arrow indicates the tumor location), 68 Ga-NYM035 showed high enrichment in tumor sites in the OS-RC-2 model, but lower uptake in tumors in the 786-O model, indicating that the drug has good tumor targeting in the OS-RC-2 model.

[0251] Example 21 Fluorescence Scanning Experiment and Fluorescence Navigation Dissection Experiment

[0252] A mouse model of human clear cell adenocarcinoma was constructed to establish an ectopic xenograft tumor model. The animal model was randomly selected and a certain amount of the fluorescent molecular drug compounds (6)-(11) and (15)-(18) of this application were administered. In vivo fluorescence scanning imaging was performed between 30 min and 120 h after administration. During the scanning, an appropriate concentration of isoflurane / air mixed gas was used for pre-anesthesia and maintenance anesthesia. The fluorescent molecular drug showed high fluorescence concentration in the tumor tissue of the tumor model mouse, and low fluorescence concentration in other tissues.

[0253] The above-mentioned mouse model was selected, and the drug was administered. Approximately 24 hours later, routine organ dissection was performed under fluorescence observation. The biodistribution of the drug in the tumor model mice showed that it was mainly excreted through the kidneys, with high fluorescence concentration in tumor tissue and lower fluorescence concentration in other tissues.

[0254] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0255] Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention. Those skilled in the art can make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, Its structure is selected from the following: （1） 、 （2） 、 （3） 、 （5） 。 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, Its structure is selected from: 。 3. A compound having a structure selected from one of the following: （13） 、 （20） 、 （24） 、 （27） 。 4. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises the compound of claim 3 and pharmaceutically acceptable excipients.

5. Use of the compound of claim 3 or the pharmaceutical composition of claim 4 in the preparation of a medicament for diagnosing and / or treating one or more tumors expressing carbonic anhydrase IX.

6. The use according to claim 5, characterized in that, The tumor was selected from cancer.

7. The use according to claim 6, characterized in that, The diagnostic method is selected from radionuclide imaging; The treatment is selected from radiotherapy; The tumors are selected from renal cell carcinoma, glioma, and other solid tumors and / or their metastatic lesions.

8. The use according to claim 7, characterized in that, The diagnostic method is selected from PET imaging and / or SPECT imaging.

9. A reagent kit, characterized in that, The kit contains the compound of claim 3 or a pharmaceutically acceptable salt thereof.

Images