Heterodimers and their radiomedical applications

Abstract

Compounds having the structures shown in the selected figures are provided. Further provided are their uses in the preparation of radionuclide labels or radionuclide-labeled reagents. Further provided are radionuclide formulations comprising compounds having the structures shown in the selected figures.

Description

[Technical Field]

[0001] This invention belongs to the field of molecular imaging, and more specifically, to heterodimers and their radiomedical applications. [Background technology]

[0002] Dual Target Strategy Currently, personalized and precise medicine are becoming cutting-edge fields in cancer treatment, creating a need for novel tumor-targeted imaging-therapy integration. Tumor-targeted imaging research has advanced dramatically, enabling non-invasive diagnosis of the disease state of clinical oncology patients and subsequent targeted treatment by utilizing highly specific peptides, antibodies, and nanoparticles as target molecules and coupling them with signaling molecules such as fluorescence and radionuclides. However, while a series of single-receptor-targeted peptides exhibit good tumor-targeting performance in the body, these peptides have drawbacks such as low binding affinity, short tumor residence time, and low tumor uptake. In some cases, the imaging contrast and specificity in tumor tissue are not ideal, and the probe retention time in tumor tissue is short, making them unfavorable for tumor diagnosis and treatment.

[0003] In contrast, dual-target molecular probes fill this gap, and because the surface of many tumor cells overexpresses multiple tumor-specific receptors, probes capable of recognizing multiple targets have higher target affinity and efficiency than single-receptor probes. Dual-target molecular probes may exhibit enhanced affinity for two receptors / proteins on the surface of cancer cells, the tumor microenvironment, or immune cells through specific interactions with two different targets. Due to improved affinity and enhanced pharmacokinetic characteristics, the specific uptake of dual-target molecular probes in tissues is superior to that of corresponding monomeric contrast agents. Therefore, a multivalent interaction strategy to convert low-affinity single-target ligands into high-affinity dual / multi-target ligands and increase maximal binding capacity is a strategy for developing novel, highly specific tumor diagnostic molecular probes.

[0004] Integrin α V β3 receptors and CD13 receptors and tumor neovascularization Angiogenesis is the process of forming new blood vessels from existing ones, and is a crucial pathway that ensures the intake of nutrients and oxygen for rapidly growing tumor tissue. It is also widely considered to be closely related to the invasion and metastasis of tumor cells. Because tumor growth and metastasis are highly dependent on angiogenesis, this phenomenon is considered a primary target for tumor diagnosis and treatment. The process of tumor angiogenesis involves integrin α V It is stimulated by various growth factors, including β3 receptors and CD13 receptors.

[0005] Integrin α V β3 plays a crucial role in tumor angiogenesis and is a receptor for extracellular matrix proteins of the RGD tripeptide sequence. These include vitreous proteins, fibronectin, fibrinogen, collagen, vascular hemophilia factor, bone bridge proteins, and adenovirus particles. V β3 is expressed at low levels in epithelial cells and mature endothelial cells, but is overexpressed in activated endothelial cells of tumor neovascularization and in some tumor cells. Studies have shown that integrin α V β3 has been shown to be highly associated with tumor growth, invasion, and metastasis processes, and is an important molecular target for the early detection and treatment of rapidly growing solid tumors.

[0006] CD13 is a membrane glycoprotein that functions as an extracellular aminopeptidase, and its specific ligand contains an NGR tripeptide sequence. High expression of CD13 can be detected in many human solid tumors, including pancreatic cancer, breast cancer, ovarian cancer, and melanoma. CD13 is also involved in tumor angiogenesis; it is present in tumor endothelial cells but not in normal tissue blood vessels.

[0007] Radioactive targeted drug therapy for tumors Radiation target therapy is an important tumor treatment method, especially applicable to metastatic and highly disseminated cancers that are ineffective for surgery or conventional radiation therapy. This therapy uses a carrier or intervention technique to specifically collect radionuclides in diseased tissues or cells. As the radiation particles from the radionuclides move in biological tissues and energy transfer and ionization occur, the energy generated in this process can directly break the chemical bonds of biological macromolecules such as nucleic acids and proteins, changing the molecular structure and function. In particular, DNA cleavage and synthesis disorders can inhibit the cell cycle of damaged cells or cause apoptosis, thus exerting a therapeutic effect. Radiation target therapy usually involves a targeting agent / carrier (such as an antibody, peptide, or small molecule, etc.) and a therapeutic radionuclide (such as 177 Lu, 90 Y, 131 I, 89 Sr, 32 P, etc., and 223Ra, 212Bi, 225Ac, etc. for emitting alpha rays), which are labeled to deliver cytotoxic doses of radioactive radiation to target cancer cells. To achieve a therapeutic effect, the half-life of currently commonly used therapeutic radionuclides is usually relatively long to achieve continuous internal radiation. For example, 177 the half-life of Lu is 6.7 days, 131 the half-life of I is 8.1 days, 32 the half-life of P is 14.3 days. To maximize the therapeutic effect of radionuclides, when designing the drug of the targeting agent / carrier, it is necessary to make its biological half-life match the radioactive half-life of the radionuclide used as a pair as much as possible. However, currently, polypeptide targeting carriers generally have the defects of low tumor uptake rate and high in vivo clearance rate. Radiation therapy using polypeptides as targeting carriers usually may have insufficient radiation dose in tumor tissues, and its application in the field of tumor treatment is limited.

[0008] Albumin carrier strategy Albumin is widely explored as a drug carrier due to its advantages such as high biocompatibility, strong non-antigenicity, good biodegradability, and ease of surface modification. To date, several albumin-based nano-administration systems have been successfully converted into clinical drugs, significantly improving drug pharmacokinetics and tumor accumulation, enhancing the therapeutic efficiency of drugs, and reducing side effects.

[0009] In the field of radiotherapy for tumors, molecular design allows for the introduction of albumin-binding fragments into carrier molecules. This enables the target molecule labeled with a radioisotope to bind to albumin in the body, significantly extending its circulation time and half-life, and improving its pharmacokinetic properties. Simultaneously, the large particle size of albumin and the EPR effect in tumor tissue can be utilized to enhance the targeting of the targeting probe and radioisotope. Furthermore, because tumor tissue has a high level of environmental metabolism, the uptake rate of nutrients such as albumin is high, thereby increasing the uptake rate of the targeting probe and radioisotope into the tumor.

[0010] However, the albumin-loading technology described above may cause side effects due to increased absorption of radioactive target peptides by healthy organs. [Overview of the project]

[0011] In some embodiments, a structure represented by formula (A) or a compound comprising the same is provided. [ka] In the formula, Z1 is -L1R1 or -H, Z2 is -L2R2 or -H, the condition being that Z1 is -L1R1 and / or Z2 is -L2R2, L1 is -(PEG)m- where m is an integer selected from 4 to 30, L2 is -(PEG)n- where n is an integer selected from 4 to 30, R1 contains a peptide sequence in which arginine, glycine or sarcosine and aspartic acid are sequentially linked, and R2 contains a peptide sequence in which asparagine, glycine or sarcosine, cysteine ​​and arginine are sequentially linked. The peptide sequence is as follows: R3 is a group represented by formula (I) or formula (II), R4 is a group represented by formula (III), formula (IV), or a long-chain fatty acid, Q1, Q2, Q3, Q4, and Q5 are each independently selected from the group consisting of -H, -F, -Cl, -Br, -I, C1-C6 linear or branched alkyl, C1-C6 linear or branched fluoroalkyl, and C1-C6 linear or branched fluoroalkoxy, and x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. [ka]

[0012] In some embodiments, the present invention provides a radionuclide preparation comprising or consisting of a compound of the present invention and a radionuclide chelated therewith.

[0013] In some embodiments, the present invention provides a method for preparing a compound or radionuclide preparation of the present invention. The method includes the steps of: obtaining a first compound having a structure represented by formula (A1); obtaining a second compound having a structure represented by formula (A2); obtaining a third compound having a group represented by formula (I'') or formula (II'') by forming an amide bond between the -N*H2 group of the second compound and the -C*OOH group of a compound represented by formula (I'), a compound represented by formula (II'), or a compound in which the -N*H2 group is protected; reacting the third compound with the first compound to obtain a fourth compound; and forming an amide bond between the -N*H2 group of the group represented by formula (I'') or formula (II'') of the fourth compound and the -C*OOH group of a compound represented by formula (III'). [ka]

[0014] In some embodiments, the present invention provides the use of the compounds of the present invention or radionuclide preparations in the preparation of drugs used for cancer detection, cancer diagnosis, cancer progression monitoring, cancer treatment monitoring, or cancer treatment.

[0015] In some embodiments, the use of the compounds of the present invention in radionuclide labeling is provided. In some embodiments, the use of the compounds of the present invention in the preparation of targeted molecules for radionuclide labeling is provided. In some embodiments, the use of the compounds of the present invention in the preparation of radionuclide labeling reagents is provided. In some embodiments, the use of the compounds of the present invention in the preparation of drug carriers is provided. In some embodiments, the use of the compounds of the present invention as drug carriers is provided. In some embodiments, the use of the compounds of the present invention or radionuclide formulations in the preparation of drugs used for cancer detection, cancer diagnosis, cancer progression monitoring, cancer treatment monitoring, or cancer treatment is provided. In some embodiments, the use of the compounds of the present invention or radionuclide formulations in cancer detection, cancer diagnosis, cancer progression monitoring, cancer treatment monitoring, or cancer treatment is provided.

[0016] In some embodiments, compounds of the present invention used for radionuclide labeling are provided. In some embodiments, targeted molecules for radionuclide labeling comprising or comprising the compounds of the present invention are provided. In some embodiments, radionuclide labeling reagents comprising or comprising the compounds of the present invention are provided. In some embodiments, drug carriers comprising or comprising the compounds of the present invention are provided. In some embodiments, formulations comprising or comprising the compounds of the present invention, radionuclide formulations, are provided for use in cancer detection, cancer diagnosis, cancer progression monitoring, cancer treatment monitoring, or cancer treatment. In some embodiments, compounds of the present invention or radionuclide formulations used in cancer detection, cancer diagnosis, cancer progression monitoring, cancer treatment monitoring, or cancer treatment are provided.

[0017] In some embodiments, methods are provided for labeling with radionuclides, comprising using the complex or radionuclide preparation in which the radionuclide has been chelated. In some embodiments, methods are provided for labeling with radionuclides, comprising bringing the complex or radionuclide preparation chelated with a radionuclide into contact with a target for radionuclide labeling. In some embodiments, methods are provided for use in cancer detection, cancer diagnosis, cancer progression monitoring, and cancer treatment monitoring. The method comprises administering the complex or radionuclide preparation chelated with a radionuclide to a subject who requires cancer detection, cancer diagnosis, cancer progression monitoring, or cancer treatment monitoring; detecting the radionuclide and determining the level and location of the radionuclide in the subject's body; and comparing the level and location with the level and location of the radionuclide in the same location on another part of an unaffected subject or in an unaffected area of ​​the subject. Here, compared to the level and location of the radionuclide in the sample of an unaffected patient or an unaffected area originating from the patient, a higher level or different location of the radionuclide in the body of the patient indicates that the patient has cancer, thereby enabling cancer detection, cancer diagnosis, monitoring of cancer progression, or monitoring of cancer treatment. In some embodiments, a method is provided for treating cancer in a patient, comprising administering the complex or radionuclide preparation in which the radionuclide has been chelated. In some embodiments, a method is provided for treating cancer in a patient, comprising exposing the patient to the complex or radionuclide preparation in which the radionuclide has been chelated. [Brief explanation of the drawing]

[0018] [Figure 1] These are electrospray mass (ESI-MS) spectra of the precursor NGR-PEG4-BCN in several embodiments of the present invention. [Figure 2] These are the electrospray mass spectra of the precursor RGD-PEG4-Lys-DOTA-N3 in several embodiments of the present invention. [Figure 3] These are the electrospray mass spectra of the precursor RGD-PEG4-Lys(-RH)-DOTA-N3 in some embodiments of the present invention. [Figure 4] These are the electrospray mass spectra of the precursor RGD-PEG4-Lys(-RH)-DOTA-click-PEG4-NGR in some embodiments of the present invention. [Figure 5] These are the electrospray mass spectra of the compound RGD-PEG4-Lys(-R-R1)-DOTA-click-PEG4-NGR in some embodiments of the present invention. [Figure 6] In several embodiments of the present invention, the uptake of 68Ga-L00, 68Ga-L11, 68Ga-L12, 68Ga-L13, and 68Ga-L21 conjugates into tumors, muscles, and kidneys at various time points after intravenous injection is shown. Here, A is uptake into tumors, B is uptake into muscles, C is uptake into kidneys, and D is a comparison of the uptake of 68Ga-L11, 68Ga-L12, 68Ga-L13, and 68Ga-L21 conjugates into tumors, muscles, and kidneys at 5 hours. The vertical axis represents the standard uptake value (SUV). [Figure 7] The uptake into tumors, muscles, and kidneys at various time points after intravenous injection of 68Ga-L00, 68Ga-L11, 68Ga-L12, 68Ga-L13, and 68Ga-L21 conjugates in several embodiments of the present invention. Here, A is the distribution in the body 5 hours after drug injection, with one representative animal selected from each conjugate group; B is the tumor / muscle ratio (tumor uptake divided by muscle uptake; expressed as a percentage) for each conjugate group at each time point; and C is the tumor / kidney ratio (tumor uptake divided by kidney uptake; expressed as a percentage) for each conjugate group at each time point. [Figure 8] These are static SPECT-CT images of mice taken 4, 24, 48, 72, and 96 hours after intravenous injection of the 177Lu-L11 compound. [Figure 9]This shows the radioactive distribution in various mouse tissues 24 hours after intravenous injection of four types of complexes: 177Lu-L11, 177Lu-L12, 177Lu-D-L11, and 177Lu-L11-1. [Figure 10] Equation (A) is given. [Modes for carrying out the invention]

[0019] In this specification, singular terms are used to refer to one or more. For example, "element" or "one element" both refer to one or more elements.

[0020] As described above, the term "approximately" refers to an approximate value that is roughly or near a given range. When used in conjunction with a numerical range, "approximately" means modifying that range by extending the limits to exceed or fall below the given numerical value. Generally, in this specification, using the term "approximately" means changing a numerical value by plus or minus 10% from the given value. On the other hand, "approximately" means adding or subtracting 20% ​​from the numerical value to which it is modified. For example, "approximately 50%" refers to a range between 45% and 55%. In this specification, numerical ranges expressed at endpoints include all integers and fractions within that range (for example, "1-5" includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). It should also be understood that all integers and their fractions are considered to be modified by the term "approximately".

[0021] As stated above, “including” or “incorporating” means that a combination (e.g., an apparatus, a composition, or a method) includes the listed elements (e.g., each unit of an apparatus, each component of a composition, or substantial steps of a method), but does not exclude other elements. When defining compositions and methods, “substantially consisting of…” means excluding other elements that are significant to the aforementioned combination. Therefore, the combinations of elements basically defined herein do not exclude other elements that do not substantially affect the substantial and novel features of the invention as claimed. “Consists of” means excluding other combinations of elements, unit components, and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the invention.

[0022] The term "amino acid" is interchangeable with "amino acid residue" and refers to both free amino acids and amino acid residues in peptides. The context will indicate whether the term refers to free amino acids or peptide residues. As used herein, "amino acid" includes naturally occurring and synthetic amino acids and is intended to include D- and L-amino acids. "Standard amino acid" typically refers to one of the 20 standard L-amino acids (including glycine) found in naturally formed peptides. The “D-” and “L-” amino acids described herein, unless otherwise specified, are not intended to exclude non-chiral amino acids, such as glycine. “Non-standard amino acid residue” refers to amino acids other than standard amino acids, whether synthetic or naturally occurring. As used herein, “synthetic amino acid” includes, but is not limited to, salts, amino acid derivatives (e.g., amides), and substituted forms, and further includes chemically modified amino acids. Amino acids in the peptides of the present invention, particularly those located at the C-terminus or N-terminus, may be modified by methylation, amidation, acetylation, or substitution with other chemical groups that do not adversely affect the activity while altering the cyclic half-life of the peptide. Furthermore, disulfide bonds may or may not be present in the peptides of the present invention.

[0023] As described herein, the term “pharmaceutical composition” means a composition comprising at least one active ingredient, which is acceptable for studying specific effective outcomes in mammals (including, for example, humans). Depending on the needs of the art, those skilled in the art can understand and grasp suitable techniques for determining whether an active ingredient has the desired efficacy.

[0024] As described herein, the term “pharmaceutically acceptable carrier” means a chemical composition that can be combined with a suitable compound or derivative and can be used to administer the suitable compound to a patient after combination.

[0025] As used herein, the term “physiologically acceptable” ester or salt means an ester or salt form of the active ingredient that is compatible with any other component of the pharmaceutical composition and is harmless to the patient receiving the composition.

[0026] As described herein, “pharmaceutically acceptable” means physiologically acceptable for use in humans or veterinary medicine.

[0027] As described herein, “pharmaceutical composition” refers to a preparation used in human or veterinary medicine.

[0028] As used herein, “multiple” means at least two.

[0029] As described herein, “polynucleotide” refers to single-stranded or parallel-stranded and antiparallel-stranded nucleic acids. Therefore, polynucleotides can be single-stranded or double-stranded nucleic acids.

[0030] As described herein, “polypeptide” means a polymer consisting of amino acid residues linked by peptide bonds, their associated native structural variants and synthetic non-natural analogs, their associated native structural variants and synthetic non-natural analogs.

[0031] As described herein, “synthetic peptide or polypeptide” refers to a peptide or polypeptide that is not naturally formed. For example, synthetic peptides or polypeptides can be synthesized using an automated peptide synthesizer.

[0032] As described herein, the term "and / or" refers to and covers any and all possible combinations of one or more related enumerated items. When used in a list of two or more items, the term "and / or" means that any one of the enumerated items may be included alone, or any combination of two or more enumerated items may be included. For example, if it is stated that a composition contains (or includes) components A, B, C and / or D, the composition may contain A alone, B alone, C alone, D alone, a combination of A and B, a combination of A and C, a combination of A and D, a combination of B and C, a combination of B and D, a combination of C and D, a combination of A, B and C, a combination of A, B and D, a combination of A, C and D, a combination of B, C and D, or a combination of A, B and C and D.

[0033] As described herein, the compounds or ions of the present invention include a plurality of variable groups. Those skilled in the art should recognize that the combinations of groups envisioned in this application are chemically acceptable combinations of compounds or ions.

[0034] As described herein, the stereochemistry of a chiral center can be defined according to the convention of those skilled in the art, namely, a wedge bond as shown by the solid line. [ka] " indicates the base pointing outwards from the page (towards the reader), and the dashed wedge-shaped bond " [ka] The symbol '' indicates a group facing inward (away from the reader). When such expression is used, it should be understood to refer to a specific single stereoisomer of the group shown in each chemical structure herein. In this specification, any bond not shown by a solid or dashed wedge should be considered not to indicate that the bond is facing outward, inward, or located on the page, but this does not prevent it from facing outward or inward where chemically acceptable.

[0035] As described herein, the term “isomer” means a compound having the same molecular formula but differing in the bonding properties or order of its atoms or the spatial arrangement of its atoms. Here, the term “stereoisomer” means an isomer with different spatial arrangements of atoms, the term “enantiomer” means a stereoisomer having one or more chiral centers and being a non-overlapping mirror image of each other, and the term “diastereomer” means a stereoisomer that does not belong to the enantiomer but has the opposite configuration of one or more chiral centers. If a compound has chiral centers, for example, if a carbon atom is bonded to four different groups, there may be a pair of enantiomers. Enantiomers are characterized by the absolute stereoconfiguration of one or more chiral centers and designated as R-configuration or S-configuration, or designated as clockwise or counterclockwise so that the molecule rotates in the plane of polarization. Chiral compounds can exist as a single enantiomer or as a mixture thereof, for example, a racemic mixture. The compounds of the present invention may contain asymmetric or chiral centers and therefore exist as different stereoisomers. All of the compounds of this application should be considered stereoisomers, including, but not limited to, diastereomers, enantiomers, and stereoisomers, as well as mixtures thereof such as racemic mixtures, and constitute part of this application.

[0036] As described herein, atoms shown in structural formulas in particular should be considered as isotopes containing that atom. For example, in this specification, hydrogen atoms (H) whether shown in letters, structural formulas, or omitted should be considered as isotopes containing hydrogen, including, but not limited to, light hydrogen, deuterium, and tritium. Similarly, in this specification, carbon atoms (C) whether shown in letters or structural formulas should be considered as isotopes containing carbon, for example, 12 C, 13 C, 14 This includes, but is not limited to, C, etc.

[0037] As described herein, particularly in the structural formulas herein, where the symbol "*" is used to label an atom, it is used solely to label a specific atom in the structural formula for the purposes described herein, and does not imply that the labeled atom has different properties not described herein.

[0038] As used herein, "(PEG)n" refers to polyethylene glycol composed of n ethylene glycol monomers. Similarly, "(PEG)m" refers to polyethylene glycol composed of four ethylene glycol monomers. For example, as used herein, "(PEG)4" refers to polyethylene glycol composed of four ethylene glycol monomers.

[0039] In some embodiments, Z1 is -L1R1. In some embodiments, Z1 is H. In some embodiments, Z2 is -L2R2. In some embodiments, Z2 is -H. In some embodiments, Z1 is -L1R1 and / or Z2 is -L2R2. In some embodiments, Z1 is -L1R1 and Z2 is -L2R2. In some embodiments, Z1 is -L1R1 and Z2 is -H. In some embodiments, Z1 is -H and Z2 is -L2R2.

[0040] In some embodiments, m is an integer selected from 4 to 30. In some embodiments, m is an integer selected from 4 to 25. In some embodiments, m is an integer selected from 4 to 20. In some embodiments, m is an integer selected from 4 to 15. In some embodiments, m is an integer selected from 4 to 10. In some embodiments, m is selected from the group consisting of 4, 5, 6, 7, and 8. In some embodiments, m is selected from the group consisting of 4, 5, and 6. In some embodiments, m is 4 or 5. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10. In some embodiments, m is 11. In some embodiments, m is 12. In some embodiments, m is 13. In some embodiments, m is 14. In some embodiments, m is 15. In some embodiments, m is 16. In some embodiments, m is 17. In some embodiments, m is 18. In some embodiments, m is 19. In some embodiments, m is 20. In some embodiments, m is 21. In some embodiments, m is 22. In some embodiments, m is 23. In some embodiments, m is 24. In some embodiments, m is 25. In some embodiments, m is 26. In some embodiments, m is 27. In some embodiments, m is 28. In some embodiments, m is 29. In some embodiments, m is 30.

[0041] In some embodiments, n is an integer selected from 4 to 30. In some embodiments, n is an integer selected from 4 to 25. In some embodiments, n is an integer selected from 4 to 20. In some embodiments, n is an integer selected from 4 to 15. In some embodiments, n is an integer selected from 4 to 10. In some embodiments, n is selected from the group consisting of 4, 5, 6, 7, and 8. In some embodiments, n is selected from the group consisting of 4, 5, and 6. In some embodiments, n is 4 or 5. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, n is 9. In some embodiments, n is 10. In some embodiments, n is 11. In some embodiments, n is 12. In some embodiments, n is 13. In some embodiments, n is 14. In some embodiments, n is 15. In some embodiments, n is 16. In some embodiments, n is 17. In some embodiments, n is 18. In some embodiments, n is 19. In some embodiments, n is 20. In some embodiments, n is 21. In some embodiments, n is 22. In some embodiments, n is 23. In some embodiments, n is 24. In some embodiments, n is 25. In some embodiments, n is 26. In some embodiments, n is 27. In some embodiments, n is 28. In some embodiments, n is 29. In some embodiments, n is 30.

[0042] In some embodiments, R1 comprises a tripeptide sequence in which arginine, glycine or sarcosine and aspartic acid are sequentially linked. In some embodiments, R1 comprises a tripeptide sequence in which L-arginine, glycine or sarcosine and L-aspartic acid are sequentially linked. In some embodiments, R1 comprises a tripeptide sequence in which L-arginine, glycine and L-aspartic acid are sequentially linked. In some embodiments, R1 comprises a tripeptide sequence in which L-arginine, sarcosine and L-aspartic acid are sequentially linked. In some embodiments, R1 is a cyclic peptide. In some embodiments, R1 is a cyclic peptide consisting of 4 to 7 amino acids. In some embodiments, R1 is a cyclic peptide consisting of 5 amino acids. In some embodiments, R1 further comprises lysine. In some embodiments, R1 is a cyclic peptide containing lysine. In some embodiments, R1 is a cyclic peptide consisting of 4 to 7 amino acids containing lysine. In some embodiments, R1 is a cyclic peptide consisting of 5 amino acids containing lysine. In some embodiments, R1 is a cyclic peptide shown in SEQ ID NO: 1 or 2. In some embodiments, R1 is a cyclic peptide shown in SEQ ID NO: 1. In some embodiments, R1 is a cyclic peptide shown in SEQ ID NO: 2.

[0043] In some embodiments, R2 comprises a tripeptide sequence in which asparagine, glycine or sarcosine and arginine are sequentially linked. In some embodiments, R2 comprises a tripeptide sequence in which L-asparagine, glycine or sarcosine and L-arginine are sequentially linked. In some embodiments, R2 comprises a tripeptide sequence in which L-asparagine, glycine and L-arginine are sequentially linked. In some embodiments, R2 comprises a tripeptide sequence in which L-asparagine, sarcosine and L-arginine are sequentially linked. In some embodiments, R2 is a cyclic peptide. In some embodiments, R2 is a cyclic peptide consisting of 4 to 7 amino acids. In some embodiments, R2 is a cyclic peptide consisting of 6 amino acids. In some embodiments, R2 further comprises lysine. In some embodiments, R2 is a cyclic peptide containing lysine. In some embodiments, R2 is a cyclic peptide consisting of 4 to 7 amino acids containing lysine. In some embodiments, R2 is a cyclic peptide consisting of 6 amino acids containing lysine. In some embodiments, R2 is a cyclic peptide shown in any one of SEQ ID NOs: 3 to 6. In some embodiments, R2 is a cyclic peptide shown in SEQ ID NO: 3. In some embodiments, R2 is a cyclic peptide shown in SEQ ID NO: 4. In some embodiments, R2 is a cyclic peptide shown in SEQ ID NO: 5. In some embodiments, R2 is a cyclic peptide shown in SEQ ID NO: 6.

[0044] In some embodiments, R3 is a group represented by formula (I). In some embodiments, R3 is a group represented by formula (II).

[0045] In some embodiments, the group represented by formula (I) is the group represented by formula (LI) or the group represented by formula (DI). In some embodiments, the group represented by formula (II) is the group represented by formula (L-II) or the group represented by formula (D-II). In some embodiments, group R is the group represented by formula (LI). In some embodiments, group R is the group represented by formula (DI). In some embodiments, group R is the group represented by formula (L-II). In some embodiments, group R is the group represented by formula (D-II). In some embodiments, group R is selected from the group consisting of the group represented by formula (LI), the group represented by formula (DI), the group represented by formula (L-II), and the group represented by formula (D-II). [ka]

[0046] In some embodiments, the compound represented by formula (I') is the compound represented by formula (L-I') or the compound represented by formula (D-I'). In some embodiments, the compound represented by formula (II') is the compound represented by formula (L-II') or the compound represented by formula (D-II). In some embodiments, the compound represented by formula (I') is the compound represented by formula (L-I'). In some embodiments, the compound represented by formula (I') is the compound represented by formula (D-I'). In some embodiments, the compound represented by formula (II') is the compound represented by formula (L-II'). In some embodiments, the compound represented by formula (II') is the compound represented by formula (D-II). In some embodiments, the group represented by formula (I'') is the group represented by formula (L-I'') or the group represented by formula (D-I''). In some embodiments, the group represented by formula (II'') is the group represented by formula (L-II'') or the group represented by formula (D-II). In some embodiments, the group represented by formula (I'') is the group represented by formula (L-I''). In some embodiments, the group represented by formula (I'') is the group represented by formula (D-I''). In some embodiments, the group represented by formula (II'') is the group represented by formula (L-II''). In some embodiments, the group represented by formula (II'') is the group represented by formula (D-II). [ka] Formula (L-I') [ka] Formula (D-I') [ka] Formula (L-II') [ka] Formula (D-II') [ka] Formula (L-I'') [ka] Formula (D-I'') [ka]

[0047] In some embodiments, R4 is a group represented by formula (III). In some embodiments, R4 is a group represented by formula (IV). In some embodiments, R4 is a long-chain fatty acid.

[0048] In some embodiments, Q1, Q2, Q3, Q4, and Q5 are each independently selected from the group consisting of -H, -F, -Cl, -Br, -I, -CH2F, -CHF2, and -CF3. In some embodiments, Q3 is selected from the group consisting of -H, -F, -Cl, -Br, -I, -CH2F, -CHF2, and -CF3. In some embodiments, one of Q1, Q2, Q3, Q4, and Q5 is -F. In some embodiments, two of Q1, Q2, Q3, Q4, and Q5 are -F. In some embodiments, Q1 is -H. In some embodiments, Q2 is -H. In some embodiments, Q3 is -F. In some embodiments, Q3 is -Cl. In some embodiments, Q3 is -Br. In some embodiments, Q3 is -I. In some embodiments, Q3 is -CH2F. In some embodiments, Q3 is -CHF2. In some embodiments, Q3 is -CF3. In some embodiments, Q4 is -F. In some embodiments, Q5 is -F. In some embodiments, Q4 is -H and Q5 is -H. In some embodiments, Q4 is -H and Q5 is -F. In some embodiments, Q4 is -F and Q5 is -H. In some embodiments, Q4 is -F and Q5 is -F.

[0049] In some embodiments, x is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. In some embodiments, x is selected from the group consisting of 1, 2, 3, 4, 5, 6, and 7. In some embodiments, x is selected from the group consisting of 1, 2, 3, 4, 5, and 6. In some embodiments, x is selected from the group consisting of 1, 2, 3, 4, and 5. In some embodiments, x is selected from the group consisting of 1, 2, 3, and 4. In some embodiments, x is selected from the group consisting of 1, 2, and 3. In some embodiments, x is selected from the group consisting of 2, 3, and 4. In some embodiments, x is selected from the group consisting of 3, 4, and 5. In some embodiments, x is 2 or 3. In some embodiments, x is 3 or 4. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3. In some embodiments, x is 4. In some embodiments, x is 5. In some embodiments, x is 6. In some embodiments, x is 7. In some embodiments, x is 8.

[0050] In some embodiments, y is selected from the group consisting of 1, 2, 3, 4, 5, and 6. In some embodiments, y is selected from the group consisting of 1, 2, 3, 4, and 5. In some embodiments, y is selected from the group consisting of 1, 2, 3, and 4. In some embodiments, y is selected from the group consisting of 1, 2, and 3. In some embodiments, y is selected from the group consisting of 2, 3, and 4. In some embodiments, y is selected from the group consisting of 3, 4, and 5. In some embodiments, y is selected from the group consisting of 4, 5, and 6. In some embodiments, y is 2 or 3. In some embodiments, y is 3 or 4. In some embodiments, y is 1. In some embodiments, y is 2. In some embodiments, y is 3. In some embodiments, y is 4. In some embodiments, y is 5. In some embodiments, y is 6.

[0051] In some embodiments, y is 3, Q1 is -H, Q2 is -H, Q3 is -CF3, Q4 is -H or -F, and Q5 is -H or -F. In some embodiments, x is 3, y is 3, Q1 is -H, Q2 is -H, Q3 is -CF3, Q4 is -H or -F, and Q5 is -H or -F. In some embodiments, R4 is a base represented by formula (IIIa), Q4 is -H or -F, and Q5 is -H or -F. [ka] Formula (IIIa).

[0052] In some embodiments, R3 is the group represented by formula (I), x is 3, R4 is the group represented by formula (IIIa), Q4 is H, and Q5 is H. In some embodiments, R3 is the group represented by formula (I), x is 3, R4 is the group represented by formula (IIIa), Q4 is F, and Q5 is H. In some embodiments, R3 is the group represented by formula (I), x is 3, R4 is the group represented by formula (IIIa), Q4 is H, and Q5 is F. In some embodiments, R3 is the group represented by formula (I), x is 3, R4 is the group represented by formula (IIIa), Q4 is F, and Q5 is F. In some embodiments, R3 is the group represented by formula (II), x is 3, R4 is the group represented by formula (IIIa), Q4 is H, and Q5 is H. In some embodiments, R3 is the group represented by formula (II), x is 3, R4 is the group represented by formula (IIIa), Q4 is F, and Q5 is H. In some embodiments, R3 is a group represented by formula (II), x is 3, R4 is a group represented by formula (IIIa), Q4 is H, and Q5 is F. In some embodiments, R3 is a group represented by formula (II), x is 3, R4 is a group represented by formula (IIIa), Q4 is F, and Q5 is F.

[0053] In some embodiments, Z1 is -L1R1 and Z2 is -L2R2, and / or m is 4, and / or n is 4. In some embodiments, x is 3, and / or R4 is a group represented by formula (III), and y is 2 or 3. In some embodiments, R4 is a group represented by formula (III), and Q1 is -H, Q2 is -H, Q3 is selected from the group consisting of -H, -F, -Cl, -Br, -I, -CH2F, -CHF2, and -CF3, and Q4 is -H or -F, and / or Q5 is -H or -F.

[0054] In some embodiments, the compounds of the present invention are chelated with radionuclides. In some embodiments, the radionuclides are 44 Sc, 47 Sc, 62 Cu, 64 Cu, 67 Cu, 66 Ga, 67 Ga,68 Ga, 86 Y, 90 Y, 89 Zr, 99m Tc, 110 mIn, 111 In, 113m In, 114m In, 177 Lu, 188 Re, 203 Pb, 212 Pb, 212 Bi, 213 Bi, 211 At, 223 Ra and 225 It comprises or consists of at least one selected from the group consisting of Ac. In some embodiments, the radionuclide is 44 Sc, 47 Sc, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 90 Y, 99m Tc, 111 In, 177 Lu, 188 Re, 212 Pb, 213 Bi, 211 At, 223 Ra and 225 It comprises or consists of at least one selected from the group consisting of Ac. In some embodiments, the radionuclide is 68 Ga and 177 It comprises or consists of at least one selected from the group consisting of Lu. In some embodiments, the radioactive nuclide is 68 It contains Ga. In some embodiments, the radioactive nuclide is 177 Includes Lu.

[0055] In some embodiments, in the step of reacting a third compound with a first compound to obtain a fourth compound, the above reaction is a click reaction.

[0056] In some embodiments, obtaining the first compound involves reacting the R2 cyclic peptide with bicyclo[6.1.0]nonine (BCN)-L2-N-hydroxysuccinimide (NHS) to obtain the first compound. In some embodiments, obtaining the second compound involves reacting the R1 cyclic peptide with a protecting group or not, L1-CH2CH2OH with a protecting group or not, lysine with a protecting group or not, and DO3AtBu-N3 to obtain the second compound. In some embodiments, the treatment is radiotherapy.

[0057] In some embodiments, the present invention has developed novel albumin-binding agents that significantly increase uptake by tumors, do not adversely affect non-tumor organs, and can improve the therapeutic index.

[0058] To further illustrate the technical means and effects employed by the present invention to achieve the desired objective, specific embodiments, structures, features, and effects of the present invention will be described in detail below with reference to the drawings and preferred embodiments.

[0059] Examples Examples and comparative examples of the present invention are shown in Table 1. Example L00 is a comparative example.

[0060] [Table 1]

[0061] The sequences of the above sequence numbers 1-6 are shown in Table 2.

[0062] [Table 2] Here, "c(...)" refers to a cyclic peptide, the lowercase regular letters indicate D-amino acids, and the italicized "Sar" indicates sarcosine.

[0063] Preparation of Compounds by Example The following examples use the compound of Example L11 as an example, but are not limited thereto. As those skilled in the art will understand, the compounds of other examples (including, but not limited to, the compounds of the examples shown in Table 1) can be synthesized by a method similar to the synthesis of the compound of Example L11.

[0064] In this specification, Example L11 may be abbreviated as "L11". The same applies to the other examples.

[0065] 1. Preparation of the precursor R2-L2-BCN 1.1. 46 μL of N,N-diisopropylethylamine (DIEA) (278 μmol) was added to 100 μL of N,N-dimethylformamide (DMF) in which 20 mg of SEQ ID NO: 3 cyclic peptide (27.78 μmol) and 22.5 mg of BCN-L2-NHS ester (41.7 μmol) were dissolved.

[0066] 1.2 The reaction mixture was stirred at room temperature for 2 hours.

[0067] 1.3. Separation of products: High-performance liquid chromatography (HPLC) was used. The stationary phase was a semi-preparative C18 column, and the mobile phase was eluted by gradient elution at a flow rate of 4 mL / min within 20 minutes from 5% acetonitrile to 50% acetonitrile.

[0068] 1.4. Identification of the product: The product was analyzed by high-performance liquid chromatography and mass spectrometry.

[0069] 1.5. Results measured by electrospray mass spectrometry: m / z[M+H] + =1144.87(Chemical formula:C 53 H 82 N 12 O 16 (Calculated molecular weight 1142.60). The electrospray mass spectrum is shown in Figure 1. The horizontal axis represents the mass-to-charge ratio (m / z), and the vertical axis represents the relative intensity (%).

[0070] 2. Preparation of the precursor R1-L1-Lys-DOTA-N3 2.1. A linear peptide, Lys(Dde)-D-Phe-Asp(Otbu)-Gly-Arg(Pbf) (i.e., a protected linear peptide of the cyclic peptide SEQ ID NO: 1), was synthesized by solid-phase synthesis, and the polypeptide chain was maintained to the resin.

[0071] 2.2 The Dde protecting group of the first lysine side chain was removed with a 2% hydrazine hydrate DMF solution.

[0072] 2.3 After washing the resin with DMF, the last Fmoc protecting group of arginine was removed with a 20% piperidine DMF solution.

[0073] 2.4 After washing the resin with DMF, Fmoc-L1-CH2CH2OH, Fmoc-Lys(Boc)-OH, and DO3AtBu-N3 were sequentially connected by solid-phase synthesis.

[0074] 2.5 After washing the resin with DMF, the resin was cleaved in a 30% trifluoroethanol dichloromethane solution for 2 hours. After filtration, the solvent was removed using a rotary evaporator to obtain a product with protecting groups.

[0075] 2.6 The product from the previous step was dissolved in dichloromethane, resulting in a 2-fold excess of benzotriazole-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBop) and a 10-fold excess of DIEA. The reaction was carried out overnight under reflux at 45°C. The solvent was removed by distillation using a rotary evaporator to obtain the cyclization product.

[0076] 2.7. Protecting groups in the product structure from the previous step were removed using a 95% TFA solution.

[0077] 2.8 The solution was purged with nitrogen and dried as much as possible, and ethyl ether was added to precipitate the product. The supernatant was removed by centrifugation. The precipitate was washed six times with ethyl ether and then evaporated at room temperature.

[0078] 2.9. Separation of products: High-performance liquid chromatography was used. The stationary phase was a semi-preparative C18 column, and the mobile phase was obtained using gradient elution at a flow rate of 4 mL / min from 5% acetonitrile to 50% acetonitrile within 20 minutes.

[0079] 2.10. Identification of the product: The product was analyzed by high-performance liquid chromatography and mass spectrometry.

[0080] 2.11. Results measured by electrospray mass spectrometry: m / z[M+H] + =1434.96(Chemical formula:C 62 H 103 N 19 O 20 (Calculated molecular weight 1433.76). The electrospray mass spectrum is shown in Figure 2. The horizontal axis is the mass-to-charge ratio (m / z), and the vertical axis is the relative intensity (%).

[0081] 3. Preparation of the precursor R1-L1-Lys(-R3-H)-DOTA-N3 3.1. Weigh 20 mg (13.94 μmol) of R1-L1-Lys-DOTA-N3 and dissolve it in 100 μL of DMF.

[0082] 3.2. 23 μL of DIEA (139.4 μmol) and 11.5 mg of the compound represented by formula (I') with the -N*H2 group protected by Boc (20.89 μmol) were sequentially added to the solution from the previous step.

[0083] 3.3 The reaction mixture was stirred at room temperature for 2 hours.

[0084] 3.4 The product from the previous step was precipitated using cold ethyl ether.

[0085] 3.5 The protecting group of the -R group in the product from the previous step was removed with a 95% TFA solution.

[0086] 3.6 The solution was purged with nitrogen and dried as much as possible, and ethyl ether was added to precipitate the product. The supernatant was removed by centrifugation. The precipitate was washed six times with ethyl ether and then evaporated at room temperature.

[0087] 3.7. Separation of products: High-performance liquid chromatography was used. The stationary phase was a semi-preparative C18 column, and the mobile phase was obtained using gradient elution at a flow rate of 4 mL / min from 5% acetonitrile to 50% acetonitrile within 20 minutes.

[0088] 3.8. Identification of the product: The product was analyzed by high-performance liquid chromatography and mass spectrometry.

[0089] 3.9. Results measured by electrospray mass spectrometry: m / z[M+2H] + =832.25(Chemical formula:C 72 H 119 N 21 O 24 (Calculated molecular weight 1661.87). The electrospray mass spectrum is shown in Figure 3. The horizontal axis represents the mass-to-charge ratio (m / z), and the vertical axis represents the relative intensity (%).

[0090] 4. Preparation of the precursor R1-L1-Lys(-R3-H)-DOTA-click-L2-R2 4.1. 15 mg (9 μmol) of R1-L1-Lys(-R3-H)-DOTA-N3 and 15 mg (13.14 μmol) of R2-L2-BCN were weighed and dissolved in 100 μL of DMF.

[0091] 4.2 The reaction mixture was stirred at room temperature for 2 hours.

[0092] 4.3. Separation of Products: High-performance liquid chromatography was used. The stationary phase was a semi-preparative C18 column, and the mobile phase was obtained using gradient elution at a flow rate of 4 mL / min, from 5% acetonitrile to 50% acetonitrile within 20 minutes.

[0093] 4.4. Identification of the product: The product was analyzed by high-performance liquid chromatography and mass spectrometry.

[0094] 4.5. Results measured by electrospray mass spectrometry: m / z[M+2H] + =1404.47(Chemical formula:C 125 H 201 N 33 O 40 (Calculated molecular weight 2804.47). The electrospray mass spectrum is shown in Figure 4. The horizontal axis is the mass-to-charge ratio (m / z), and the vertical axis is the relative intensity (%).

[0095] 5. Preparation of the R1-L1-Lys(-R3-R4)-DOTA-click-L2-R2 conjugate 5.1 12 mg (4.28 μmol) of R1-L1-Lys(-R3-H)-DOTA-click-L2-R2 was weighed and dissolved in 100 μL of DMF.

[0096] 5.2. 7 μL of DIEA (42.8 μmol) and 5.6 mg of the compound represented by formula (III') (17 μmol) were added sequentially to the solution from the previous step.

[0097] 5.3 The reaction mixture was stirred at room temperature for 2 hours.

[0098] 5.4. A 1M TFA aqueous solution was added to the reaction mixture to adjust the pH of the reaction solution to 5.0-6.0.

[0099] 5.5. Separation of products: High-performance liquid chromatography was used. The stationary phase was a semi-preparative C18 column, and the mobile phase was obtained using gradient elution at a flow rate of 4 mL / min, from 20% acetonitrile to 32% acetonitrile within 20 minutes.

[0100] 5.6. Identification of the product: The product was analyzed by high-performance liquid chromatography and mass spectrometry.

[0101] 5.7. Results measured by electrospray mass spectrometry: m / z[M+2H] +=1510.58(Chemical formula:C 136 H 210 F3N 33 O 41 (Calculated molecular weight 3018.53). The electrospray mass spectrum is shown in Figure 5. The horizontal axis is the mass-to-charge ratio (m / z), and the vertical axis is the relative intensity (%).

[0102] stability studies In the experiment, the stability of Example L11 compound (1.0 μg / mL) in mouse plasma or PBS was studied using an in vitro constant temperature (37°C) incubation method. Example L11 compound was dissolved in 1 mL of mouse serum and incubated in vitro at constant temperature for 0 h, 0.5 h, 1 h, 4 h, 24 h, and 48 h, after which the percentage of drug residue was measured. PBS was used as the negative control group. The peak areas of the drug and internal standard were measured by LC-MS / MS, and the ratio of these peak areas was calculated as a substitute for the drug concentration.

[0103] The results are shown in Table 3.

[0104] Table 3: Percentage of drug residue after in vitro constant temperature incubation in mouse plasma or PBS of the L11 compound in Example. [Table 3]

[0105] As can be seen from the table above, the compound L11 in Example retained a drug residue percentage of almost 95% or more after in vitro constant-temperature incubation in mouse plasma or PBS, demonstrating its high stability.

[0106] Animal experiments 1. Construction of a human pancreatic cancer xenograft tumor model BxPC3 human pancreatic cancer cells were placed in a mixture of 200 μL of phosphate buffer and matrix gel (v / v, 1 / 1), and 2 × 10⁻¹⁶ cells were placed in the mixture. 6Individual cells were inoculated subcutaneously into the left shoulder of normal NCr nude mice (18 - 25 g, 4 - 6 weeks old). After an average of 1.5 weeks, the tumor diameter reached approximately 10 mm, which was already large enough for in vivo distribution and SPECT / CT imaging studies.

[0107] 2. 68 Ga labeling 2.1. 1.0 μmol of the compound of Example L11 was dissolved in 1.0 mL of 0.25 M sodium acetate solution.

[0108] 2.2. The gallium germanium generator was eluted with 4 mL of 0.05 M hydrochloric acid solution to prepare the rinse solution 68 GaCl3.

[0109] 2.3. 1 μmol of the solution of the compound of Example L11 was added to the rinse solution with a radioactivity of 1 mCi, and further 300 μL of 0.25 M sodium acetate solution was added, and the reaction was carried out at 60 °C for 10 min, 68 to obtain the Ga - L11 complex. The resulting mixture was monitored by radioactivity high - performance liquid chromatography to quantify the label (purity > 97%).

[0110] 3. Small animal positron emission computed tomography (PET - CT) PET - CT and image analysis were performed using a small animal NovelMedcal PET - CT scanner (Beijing Yongxin). The maximum full - width at half - maximum in the tangential and radial directions at the center of the field of view was 1.5 mm, and the maximum full - width at half - maximum in the tangential and radial directions at the edge of the field of view was 1.8 mm.

[0111] After anesthesia with isoflurane, approximately 100 μCi of 68 Ga - L00, 68 Ga - L11, 68 Ga - L12, 68 Ga - L13 and 68Ga-L21 complexes were injected via tail vein into BxPC3 tumor-bearing mice. Each complex was injected into four mice. Static PET-CT images were acquired at 0.5, 1, 2, 3, 4, 5, and 6 hours after intravenous injection, each lasting 15 minutes. The imaging effects of the five different complexes at each time point were compared.

[0112] PET and CT images are acquired using NMSoft workstation software (Beijing Yongxin). Data are given as the percentage of injection volume per gram of tissue or organ (ID / g), determined by attenuation correction for each sample (normalized to a known weight representing the injection volume). Normalization is performed at statistical time, and normalized uptake values ​​(SUVs) are calculated using the following formula. SUV=([Bq / mL]×[Animal weight (g)] / [Injection amount (Bq)]) Figures 6 and 7 show the uptake of the five complexes into tumors, muscles, and kidneys at different time points.

[0113] For the 68Ga-L00 complex formed with the Example L00 conjugate, which lacked an albumin-binding fragment in its conjugate structure, the drug was rapidly metabolized by the kidney within 2 hours after injection, resulting in a weakened signal in tumor tissue and a tumor / kidney ratio of only about 0.18 after 2 hours.

[0114] After injecting the other four complexes, signals could be detected in the blood of mice throughout the body within a short time, demonstrating that the albumin-binding fragments in the complexes exerted their effect, increasing the circulating time of the complexes in the body. Furthermore, as time increased, most of the complexes were excreted in the urine by the kidneys, and the background signal in normal tissues gradually decreased, while the signal in tumor tissues gradually increased, indicating that the complexes concentrated specifically in tumor tissues over time.

[0115] Formed with compound L11 in Example 68 For the Ga-L11 complex, the tumor / kidney ratio reached approximately 1.4 6 hours after injection and continued to increase, demonstrating that the L11 compound in Example has good stability, targetability, and specificity.

[0116] 68 After injecting the Ga-L12 complex, the overall imaging trend was 68 similar to that of the Ga-L11 complex, but the accumulation in tumor tissues after 5-6 hours was 68 not as obvious as that of the Ga-L11 complex.

[0117] 68 The Ga-L13 complex also showed a similar trend, but the uptake rate in the whole tumor tissue was 68 lower than that of the Ga-L11 complex.

[0118] 68 For the Ga-L21 complex, the Example L21 conjugate has the same important polypeptide target and albumin-binding fragment in the structure as the Example L21 conjugate, and since there is a difference in one linker structure, the tissue distribution trends and degrees of both are very similar.

[0119] Figure 7A shows the in vivo distribution 5 hours after injecting the drug, with one representative animal selected from each complex group.

[0120] As can be seen from the MIP images and the quantitative results of the tumor, kidney, and muscle ROI regions, 68 the tumor / kidney ratio and tumor / muscle ratio of the Ga-L11 complex were the highest among the five conjugates. Also, 68 compared with the Ga-L00 complex, the in vivo stability and tumor tissue accumulation of the other four complexes were significantly improved.

[0121] 4. 177 Lu labeling 6 μL of a 0.5 nmol / μL solution of the Example L11 compound was added to 1 mCi of 177LuCl3, and the buffer was 200 μL of 0.1 M acetic acid-ammonium acetate buffer (pH = 3.7 - 4.0), and then heated at 90 °C for 15 minutes.

[0122] The resulting mixture was monitored and quantitatively labeled (>97%) by high-performance radiative liquid chromatography. 177 A Lu-L11 composite can be obtained.

[0123] 5. Single-photon emission computed tomography (SPECT-CT) of small animals SPECT-CT and image analysis were performed using a small animal NovelMedcal SPECT-CT scanner (Beijing Yongxin). The maximum half-width in the tangential and radial directions at the center of the field of view was 1.5 mm, and the maximum half-width in the tangential and radial directions at the edges of the field of view was 1.8 mm.

[0124] After anesthetizing with isoflurane, approximately 500 μCi 177 The Lu-L11 complex was injected into the tail vein of BxPC3 tumor-bearing mice. A total of four animals were injected. Static SPECT-CT images were acquired at 4, 24, 48, 72, and 96 hours after intravenous injection, each lasting 30 minutes. 177 The long-term imaging effects of the Lu-L11 complex were evaluated.

[0125] The SPECT-CT imaging results are shown in Figure 8. 177 Within four days of intravenous injection of the Lu-L11 solution, radioactive signals could be continuously detected in mouse tumor tissue, while the signals disappeared in other tissues and organs. The example L11 compound demonstrates good in vivo stability and targetability, and is a therapeutic radionuclide with a long half-life. 177 This suggests that it may have potential use in combination with Lu for radiotherapy of tumors.

[0126] 6. In vivo distribution studies Examples 177 Lu-L11, 177 Lu-L12, 177 Lu-D-L11, 177 Lu-L11-1 complex (3.7 MBq) was intravenously injected into BxPC3 tumor-bearing NCr nude mice. Five mice were euthanized at 1, 4, 24, 48, 72, and 120 hours after administration, and samples were subsequently dissected.

[0127] The number of tissues and organs of interest collected and weighted and radiometrically counted using a gamma counter.

[0128] Figure 9 shows 177 Lu-L11, 177 Lu-L12, 177 Lu-D-L11, 177 This graph shows the radioactive distribution in various tissues of mice 24 hours after intravenous injection of four different Lu-L11-1 complexes. Here, the values ​​on the vertical axis are given as the percentage of injected volume per gram of tissue or organ (ID / g), and are determined by attenuation correction for each sample (normalized to a known weight representing the injected volume).

[0129] As can be seen from Figure 9, 24 hours after intravenous injection, 177 Lu-L11, 177 Lu-L12, 177 Lu-D-L11, 177 All four types of Lu-L11-1 complexes are concentrated in tumors, and of these, 177 The concentration of Lu-L12 was higher than that of the other three types of complexes. These complexes were also concentrated to some extent in the kidneys, and relatively less so in the spleen and uterus.

[0130] 7.Statistical analysis Statistical analysis was performed using a two-tailed unpaired t-test in GraphPad 6. A probability (p) value less than 0.05 is considered statistically significant.

[0131] The embodiments described above are merely preferred embodiments of the present invention and do not limit the scope of protection of the present invention. Any substantial changes and substitutions made by those skilled in the art based on the present invention are all included within the scope of protection of the present invention.

Claims

1. A compound characterized by containing the structure shown in formula (A) below. 【Chemistry 1】 (In the formula, The said Z １ is -L １ R １ or -H, and the said Z ２ is -L ２ R ２ or -H, and the condition is that the said Z １ is -L １ R １ and / or the said Z ２ is -L ２ R ２ is the case. Said L １ Ha- (PEG) ｍ - and the above m is an integer selected from 4 to 30, Said L ２ Ha- (PEG) ｎ - and the above n is an integer selected from 4 to 30, The aforementioned R １ It contains a peptide in which arginine, glycine or sarcosine, and aspartic acid are sequentially linked. The aforementioned R ２ It contains a peptide in which asparagine, glycine or sarcosine, cysteine, and arginine are sequentially linked. The aforementioned R ３ is a group represented by formula (I) or formula (II) below, 【Chemistry 2】 The aforementioned R ４ is a group represented by formula (III), a group represented by formula (IV), or a long-chain fatty acid. 【Transformation 3】 The aforementioned Q １ , the aforementioned Q ２ , the aforementioned Q ３ , the aforementioned Q ４ , and the aforementioned Q ５ These are independently -H, -F, -Cl, -Br, -I, and C. １ -C ６ Linear or branched alkyl, C １ -C ６ Linear or branched fluoroalkyl groups, and C １ -C ６ Selected from the group consisting of linear or branched fluoroalkoxys, The aforementioned x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. The aforementioned y is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6.

2. The compound according to claim 1, characterized in that R2 is a cyclic peptide shown in any one of SEQ ID NOs: 3 to 6.

3. The compound according to claim 1, characterized in that R2 is a cyclic peptide shown in any one of SEQ ID NOs: 3, 4, or 6.

4. The compound according to claim 1, characterized in that R1 is a cyclic peptide shown in SEQ ID NO: 1 or 2.

5. The R1 is a cyclic peptide and further comprises lysine, and / or The compound according to claim 1, characterized in that R2 is a cyclic peptide and further contains lysine.

6. Said Z １ Ha-L １ R １ and the aforementioned Z ２ Ha-L ２ R ２ and / or The aforementioned m is 4 and / or The compound according to claim 1, characterized in that n is 4.

7. The above x is 3 and / or The aforementioned R ４ The compound according to claim 1, characterized in that is a group represented by formula (III), and y is 2 or 3.

8. The aforementioned R ４ is a base represented by formula (III), The aforementioned Q １ is -H, and the above Q ２ is -H, and the above Q ３ -H, -F, -Cl, -Br, -I, -CH ２ F, -CHF ２ and -CF ３ Selected from the group consisting of the above Q ４ is -H or -F, and / or the aforementioned Q ５ is -H or -F The compound according to claim 1, characterized in that it is a compound according to claim 1.

9. A compound according to any one of claims 1 to 8, A radionuclide chelated with the aforementioned compound, A radionuclide preparation characterized by containing [a specific substance].

10. The aforementioned radioactive nuclides are, ４４ Sc, ４７ Sc, ６２ Cd, ６４ Cd, ６７ Cd, ６６ Ga, ６７ Ga, ６８ Ga, ８６ Y, ９０ Y, ８９ Zr, ９９ｍ Tc, １１０ｍ In, １１１ In, １１３ｍ In, １１４ｍ In, １７７ Lu, １８８ Re, ２０３ Pb, ２１２ Pb, ２１２ Bi, ２１３ Bi, ２１１ At, ２２３ Ra and ２２５ The radionuclide preparation according to claim 9, characterized by comprising at least one selected from the group consisting of Ac.

11. A method for preparing the compound according to any one of claims 1 to 8, A step of obtaining a first compound having the structure represented by the following formula (A1), 【Chemistry 4】 The steps include obtaining a second compound having the structure shown in formula (A2) below, 【Transformation 5】 -N*H of the second compound ２ A group and the compound represented by the following formula (I') or the compound represented by the following formula (II') or its -N*H ２ The steps include: obtaining a third compound having a group represented by the following formula (I'') or a group represented by the following formula (II'') by forming an amide bond with the -C*OOH group of a protected compound; 【Transformation 6】 The steps include reacting the third compound with the first compound to obtain a fourth compound, The group represented by formula (I'') or the group represented by formula (II'') of the fourth compound -N*H ２ The steps include: forming an amide bond between the group and the -C*OOH group of the compound represented by the following formula (III'), 【Transformation 7】 A preparation method characterized by including the following.

12. A pharmaceutical composition used for radionuclide labeling, cancer detection, cancer diagnosis, cancer progression monitoring, cancer treatment monitoring, or cancer treatment, characterized by comprising a compound according to any one of claims 1 to 8.

Images