Heterodimers and their radioactive medical 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] The present invention is in the field of molecular imaging, and more specifically relates to heterodimers and their radiomedical applications. [Background technology]

[0002] Dual Target Strategy As personalized and precision medicine has become a frontier in cancer treatment, a need has arisen for novel tumor-targeted imaging-therapy integration. Currently, tumor-targeted imaging research has made great strides. By using highly specific peptides, antibodies, and nanoparticles as targeting molecules and coupling them with signal molecules such as fluorescent and nuclides, it has become possible to non-invasively diagnose the disease state of clinical tumor patients and then administer targeted treatment. However, although a number of single-receptor targeting peptides have demonstrated good tumor targeting capabilities in the body, these single-receptor targeting peptides suffer from drawbacks such as low binding affinity, short tumor retention time, and low tumor uptake. In some cases, they suffer from issues such as less than ideal imaging contrast and specificity in tumor tissue and short probe retention time in tumor tissue, which are disadvantageous for tumor diagnosis and treatment.

[0003] In contrast, dual-targeting molecular probes fill this void. Because many tumor cells overexpress multiple tumor-specific receptors on their surfaces, probes that can distinguish between multiple targets have higher target affinity and efficiency than single-receptor probes. Dual-targeting molecular probes may exhibit enhanced affinity through specific interactions with two different targets: two receptors / proteins on the cancer cell surface, the tumor microenvironment, or immune cells. Due to their improved affinity and pharmacokinetic characteristics, the specific uptake of dual-targeting molecular probes in tissues is superior to that of corresponding monomeric contrast agents. Therefore, multivalent interaction strategies to convert low-affinity single-targeting ligands into high-affinity dual / multi-targeting ligands and increase maximum binding capacity are key strategies for developing novel, highly specific tumor diagnostic molecular probes.

[0004] Integrin α V β3 receptors and CD13 receptors and tumor angiogenesis Angiogenesis is the process of forming new blood vessels from existing blood vessels. It is an important pathway to ensure that rapidly growing tumor tissues receive nutrients and oxygen, and is also widely considered to be an important link between tumor cell invasion and metastasis. Because tumor growth and metastasis depend heavily on angiogenesis, this phenomenon is considered a major target for tumor diagnosis and therapy. The tumor angiogenesis process is mediated by integrin α V It is stimulated by a variety of growth factors, including β3 receptors and CD13 receptors.

[0005] Integrin α V Integrin α plays an important role in tumor angiogenesis and is a receptor for extracellular matrix proteins with the RGD tripeptide sequence, including vitreous protein, fibronectin, fibrinogen, collagen, vascular hemophilic factor, bone bridge protein, and adenovirus particles. V Integrin α3 is expressed at low levels in epithelial cells and mature endothelial cells, but is overexpressed in activated endothelial cells of tumor neovasculature and in some tumor cells. V β3 is highly associated with tumor growth, invasion and metastatic processes and has emerged as 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 the NGR tripeptide sequence. High expression of CD13 can be detected in many human solid tumors, including those of pancreatic cancer, breast cancer, ovarian cancer, and melanoma. CD13 is also involved in tumor angiogenesis, and CD13 is present on tumor endothelial cells but not on normal tissue blood vessels.

[0007] Radiotargeted drug therapy of tumors Targeted radiation therapy is an important tumor treatment method, especially for metastatic and highly diffused cancers that are ineffective against surgery or conventional radiation therapy. This therapy utilizes carriers or intervention techniques to specifically collect radionuclides in diseased tissues or cells, and the radiation particles from the radionuclides move in biological tissues, causing energy transfer and ionization. The energy generated in this process can directly cleave the chemical bonds of biological macromolecules such as nucleic acids and proteins, changing their molecular structure and function. In particular, DNA cleavage and synthesis disorders can inhibit the cycle of damaged cells or cause apoptosis, thereby exerting a therapeutic effect. Targeted radiation therapy usually involves the combination of a targeting agent / carrier (e.g., antibody, peptide, or small molecule) and a therapeutic radioisotope (e.g., a β-ray emitting radioisotope). 177 Lu, 90 Y, 131 I, 89 Sr, 32 They are labeled with radionuclides (e.g., P, and α-ray emitting 223Ra, 212Bi, 225Ac, etc.) to deliver cytotoxic doses of radioactive radiation to target cancer cells. To achieve therapeutic effects, the half-lives of currently commonly used therapeutic radionuclides are usually relatively long, resulting in sustained internal emission. 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, the biological half-life of the targeting agent / carrier must be matched as closely as possible to the radioactive half-life of the radionuclide used as a pair. However, currently, polypeptide targeting carriers generally suffer from the drawbacks of low tumor uptake and high body clearance. Radiotherapy using polypeptides as targeting carriers usually results in insufficient radiation doses in tumor tissue, limiting its application in the field of tumor treatment.

[0008] Albumin Carrier Strategy Albumin has been widely explored as a drug carrier due to its advantages of high biocompatibility, strong non-antigenicity, good biodegradability, and ease of surface modification. To date, several albumin-based nanodelivery systems have been successfully converted into clinical drugs, significantly improving drug pharmacokinetics and tumor accumulation, thereby increasing the therapeutic efficacy of drugs and reducing side effects.

[0009] In the field of tumor radiotherapy, molecular design can introduce albumin binding fragments into carrier molecules, so that radioisotope-labeled targeting molecules can bind to albumin in the body, significantly extending their circulation time and half-life, and improving their pharmacokinetic properties.At the same time, the large particle size of albumin and the EPR effect of tumor tissue can be used to enhance the targeting of targeting probes and radioisotopes, and the high metabolic level of tumor tissues allows for a high uptake rate of nutrients such as albumin, thereby increasing the uptake rate of targeting probes and radioisotopes into tumors.

[0010] However, the albumin-loading technique may cause side effects due to increased uptake of radioactive target peptides by healthy organs. Summary of the Invention

[0011] In some embodiments, compounds are provided that consist of or have a structure represented by Formula (A): [ka] wherein Z1 is -L1R1 or -H, Z2 is -L2R2 or -H, provided that Z1 is -L1R1 and / or Z2 is -L2R2, L1 is -(PEG)m- and m is an integer selected from 4 to 30, L2 is -(PEG)n- and n is an integer selected from 4 to 30, R1 comprises a peptide sequence in which arginine, glycine or sarcosine, and aspartic acid are sequentially linked, and R2 comprises a peptide sequence in which asparagine, glycine or sarcosine, cysteine, and arginine are sequentially linked. wherein R3 is a group represented by formula (I) or a group represented by formula (II), R4 is a group represented by formula (III), a group represented by 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 straight-chain or branched alkyl, C1-C6 straight-chain or branched fluoroalkyl, and C1-C6 straight-chain 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 formulation comprising or consisting of a compound of the present invention and a radionuclide chelated thereto.

[0013] In some embodiments, the present invention provides a method for preparing a compound or radionuclide formulation of the present invention, the method comprising 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), forming an amide bond between the -N*H 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*H group is protected, to obtain a third compound having a group represented by Formula (I") or (II"), reacting the third compound with the first compound to obtain a fourth compound, and forming an amide bond between the -N*H group of the group represented by Formula (I") or (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 a compound or radionuclide formulation of the present invention in the preparation of a medicament for use in the detection of cancer, the diagnosis of cancer, the monitoring of cancer progression, the monitoring of cancer therapy, or the treatment of cancer.

[0015] In some embodiments, there is provided the use of a compound of the present invention in radionuclide labeling. In some embodiments, there is provided the use of a compound of the present invention in preparing a radionuclide-labeled targeting molecule. In some embodiments, there is provided the use of a compound of the present invention in preparing a radionuclide-labeled reagent. In some embodiments, there is provided the use of a compound of the present invention in preparing a drug carrier. In some embodiments, there is provided the use of a compound of the present invention as a drug carrier. In some embodiments, there is provided the use of a compound or radionuclide formulation of the present invention in preparing a drug for use in the detection of cancer, the diagnosis of cancer, monitoring cancer progression, monitoring cancer therapy, or the treatment of cancer. In some embodiments, there is provided the use of a compound or radionuclide formulation of the present invention in the detection of cancer, the diagnosis of cancer, monitoring cancer progression, monitoring cancer therapy, or the treatment of cancer.

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

[0017] In some embodiments, a method for labeling with a radionuclide is provided, comprising using the radionuclide-chelated conjugate or radionuclide formulation. In some embodiments, a method for labeling with a radionuclide is provided, comprising contacting the radionuclide-chelated conjugate or radionuclide formulation with a radionuclide-labeled target. In some embodiments, a method for use in cancer detection, cancer diagnosis, cancer progression monitoring, or cancer treatment monitoring is provided. The method includes administering the radionuclide-chelated conjugate or radionuclide formulation to a subject in need of cancer detection, cancer diagnosis, cancer progression monitoring, or cancer treatment monitoring; detecting the radionuclide; 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 an otherwise identical location in an unaffected subject or in an unaffected area of ​​the subject. wherein a higher level or different location of the radionuclide in the body of the test or treated subject compared to the level and location of the radionuclide in an unaffected subject or in the sample from an unaffected region derived from the test or treated subject indicates that the subject is afflicted with cancer, thereby detecting cancer, diagnosing cancer, monitoring cancer progression, or monitoring cancer treatment. In some embodiments, methods are provided for treating cancer in a patient comprising administering the radionuclide-chelated conjugate or radionuclide formulation. In some embodiments, methods are provided for treating cancer in a patient comprising contacting the patient with the radionuclide-chelated conjugate or radionuclide formulation. [Brief explanation of the drawings]

[0018] [Figure 1] 1 shows an electrospray mass spectrometry (ESI-MS) spectrum of the precursor NGR-PEG4-BCN in some examples of the present invention. [Figure 2] 1 shows an electrospray mass spectrum of the precursor RGD-PEG4-Lys-DOTA-N3 in some examples of the present invention. [Figure 3] 1 shows an electrospray mass spectrum of the precursor RGD-PEG4-Lys(-RH)-DOTA-N3 in some examples of the present invention. [Figure 4] Electrospray mass spectrum of the precursor RGD-PEG4-Lys(-RH)-DOTA-click-PEG4-NGR in some examples of the present invention. [Figure 5] 1 shows an electrospray mass spectrum of the compound RGD-PEG4-Lys(-R-R1)-DOTA-click-PEG4-NGR in some examples of the present invention. [Figure 6] In some examples of the present invention, tumor, muscle, and kidney uptake at various time points after intravenous injection of 68Ga-L00, 68Ga-L11, 68Ga-L12, 68Ga-L13, and 68Ga-L21 conjugates are shown. Here, A is tumor uptake, B is muscle uptake, C is kidney uptake, and D is a comparison of tumor, muscle, and kidney uptake of 68Ga-L11, 68Ga-L12, 68Ga-L13, and 68Ga-L21 conjugates at 5 hours. The vertical axis represents the standard uptake value (SUV). [Figure 7] Figure 1 shows tumor, muscle, and kidney uptake at various time points after intravenous injection of 68Ga-L00, 68Ga-L11, 68Ga-L12, 68Ga-L13, and 68Ga-L21 conjugates in some examples of the present invention, where A is the biodistribution status of one representative animal selected from each conjugate group 5 hours after drug injection, 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] 1 shows static SPECT-CT images of mice 4, 24, 48, 72, and 96 hours after intravenous injection of 177Lu-L11 compound. [Figure 9]This shows the radioactivity 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] Formula (A). DETAILED DESCRIPTION OF THE INVENTION

[0019] As used herein, the terms "a," "an," and "an element" refer to one or more elements.

[0020] As stated above, the term "about" refers to an approximation of a value that is roughly or nearby in range. When the term "about" is used in conjunction with a numerical range, it refers to modifying that range by extending the limits above or below the stated numerical values. Generally, the use of the term "about" herein varies a numerical value by plus or minus 10% from the stated value. Conversely, the term "about" refers to adding or subtracting 20% ​​from the modified numerical value. For example, "about 50%" refers to a range of 45%-55%. Numerical ranges expressed herein by endpoints include all integers and fractions within this range (e.g., "1 to 5" includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). It should also be understood that all integers and fractions thereof are considered to be modified by the term "about."

[0021] As stated above, "comprise" or "comprising" means that a combination (e.g., an apparatus, composition, or method) includes listed elements (e.g., each unit of an apparatus, each component of a composition, or a substantial step of a method), but does not exclude other elements. When defining compositions and methods, "consisting essentially of" means excluding other elements that are significant to the intended combination. Thus, a combination of elements essentially defined herein does not exclude other elements that do not materially affect the substantial and novel characteristics of the claimed invention. "Consisting 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" can be used interchangeably with "amino acid residue" and refers to free amino acids and peptide amino acid residues. The context will indicate whether the term refers to a free amino acid or a peptide residue. As used herein, "amino acid" includes naturally occurring and synthetic amino acids and is intended to include both D- and L-amino acids. A "standard amino acid" typically refers to any of the 20 standard L-amino acids (including glycine) found in naturally occurring peptides. The terms "D-" and "L-" amino acids used herein are not intended to exclude non-chiral amino acids, such as glycine, unless otherwise specified. A "non-standard amino acid residue" refers to an amino acid other than a standard amino acid, whether synthetic or naturally occurring. As used herein, "synthetic amino acid" further includes chemically modified amino acids, including, but not limited to, salts, amino acid derivatives (e.g., amides), and substitutions. Amino acids contained in the peptides of the present invention, particularly those located at the C- or N-terminus, may be modified by methylation, amidation, acetylation, or substitution with other chemical groups that alter the circulating half-life of the peptide without adversely affecting its activity. Additionally, disulfide bonds may or may not be present in the peptides of the present invention.

[0023] As used herein, the term "pharmaceutical composition" refers to a composition containing at least one active ingredient, which is acceptable for studying a specific effective outcome in a mammal (including, for example, a human). As needed by the artisan, those skilled in the art will understand and comprehend techniques suitable for determining whether an active ingredient has a desired effective effect.

[0024] As used herein, the term "pharmaceutically acceptable carrier" refers to a chemical composition that can be combined with a suitable compound or derivative and, after combination, can be applied to administer the suitable compound to a subject.

[0025] As used herein, the term "physiologically acceptable" ester or salt refers to an ester or salt form of an active ingredient that is compatible with any other ingredients of the pharmaceutical composition, and such form is not harmful to the subject to whom the composition is administered.

[0026] As used herein, "pharmaceutically acceptable" refers to physiologically acceptable for human or veterinary use.

[0027] As used herein, a "pharmaceutical composition" refers to a formulation for use in human or veterinary medicine.

[0028] As used herein, "plurality" refers to at least two.

[0029] As used herein, a "polynucleotide" refers to a single strand or parallel and anti-parallel strands of a nucleic acid. Thus, a polynucleotide can be a single-stranded or double-stranded nucleic acid.

[0030] As used herein, "polypeptide" refers to a polymer of amino acid residues joined by peptide bonds, and related naturally occurring structural variants and synthetic non-naturally occurring analogues thereof.

[0031] As used herein, a "synthetic peptide or polypeptide" refers to a non-naturally formed peptide or polypeptide. For example, a synthetic peptide or polypeptide can be synthesized using an automated peptide synthesizer.

[0032] As used herein, the term "and / or" refers to and covers any and all possible combinations of one or more associated listed items. When used in a list of two or more items, the term "and / or" means that any one of the listed items may be present alone, or any combination of two or more of the listed items may be present. For example, when a composition is described as comprising components A, B, C, and / or D, the composition may comprise A alone, B alone, C alone, D alone, a combination comprising A and B, a combination comprising A and C, a combination comprising A and D, a combination comprising B and C, a combination comprising B and D, a combination comprising C and D, a combination comprising A, B, and C, a combination comprising A, B, and D, a combination comprising A, C, and D, a combination comprising B, C, and D, or a combination comprising A, B, C, and D.

[0033] As described herein, the compounds or ions of the present invention contain multiple variables. One skilled in the art will recognize that combinations of groups envisioned in this application are chemically permissible combinations of compounds or ions.

[0034] As used herein, the stereochemistry of a chiral center can be defined according to the convention of one skilled in the art, i.e., as indicated by a solid wedged bond " [ka] " indicates a group pointing outward from the page (toward the reader), and a dashed wedge bond " [ka] " indicates a group pointing into the plane of the paper (away from the reader). When such expressions are used, it can be understood to refer to a specific single stereoisomer of the group shown in each chemical structure herein. Any bond herein that is not shown with a solid wedge bond or a dashed wedge bond should be considered as not specifically indicating that the bond is pointing out of the plane of the paper, in the plane of the paper, or located in the plane of the paper, but does not preclude it from pointing out of the plane of the paper or in the plane of the paper when chemically permissible.

[0035] As used herein, the term "isomer" refers to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Here, the term "stereoisomer" refers to isomers that differ in the arrangement of their atoms in space, the term "enantiomer" refers to stereoisomers with one or more asymmetric centers that are non-superimposable mirror images of each other, and the term "diastereomer" refers to stereoisomers that have opposite configurations at one or more asymmetric centers. When a compound has an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of enantiomers may exist. Enantiomers are characterized by the absolute configuration of their asymmetric center(s) and are designated as R- or S-configuration, or as right-handed or left-handed, depending on how the molecule rotates the plane of polarized light. Chiral compounds can exist as single enantiomers or mixtures thereof, such as racemic mixtures. The compounds of the present invention may contain asymmetric or chiral centers and therefore exist as different stereoisomers. All stereoisomers of the compounds of this application, including but not limited to diastereomers, enantiomers, and stereoisomers, and mixtures thereof, such as racemic mixtures, are to be considered and form part of this application.

[0036] As described herein, in particular, any atom shown in a structural formula herein should be considered as each isotope containing that atom. For example, any hydrogen atom (H) shown in a letter, structural formula, or omitted herein should be considered as each isotope containing hydrogen, including, but not limited to, protium, deuterium, tritium, etc. Any carbon atom (C) shown in a letter or structural formula herein should be considered as each isotope containing carbon, including, for example, 12 C. 13 C. 14 Including, but not limited to, C.

[0037] As described herein, particularly in structural formulae herein, when the symbol "*" is used to label an atom, it is only used to label a particular atom in a structural formula for purposes of explanation in this application and does not imply that the labeled atom has different properties not explained in this application.

[0038] As used herein, "(PEG)n" refers to polyethylene glycol consisting of n ethylene glycol monomers. The same applies to "(PEG)m" as used herein. For example, as used herein, "(PEG)4" refers to polyethylene glycol consisting 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, glycine, 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 set forth in SEQ ID NO: 1 or 2. In some embodiments, R1 is a cyclic peptide set forth in SEQ ID NO: 1. In some embodiments, R1 is a cyclic peptide set forth 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 set forth in any one of SEQ ID NOs: 3 to 6. In some embodiments, R2 is a cyclic peptide set forth in SEQ ID NO: 3. In some embodiments, R2 is a cyclic peptide set forth in SEQ ID NO: 4. In some embodiments, R2 is a cyclic peptide set forth in SEQ ID NO: 5. In some embodiments, R2 is a cyclic peptide set forth 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 a group represented by formula (LI) or a group represented by formula (DI). In some embodiments, the group represented by formula (II) is a group represented by formula (L-II) or a group represented by formula (D-II). In some embodiments, the group R is a group represented by formula (LI). In some embodiments, the group R is a group represented by formula (DI). In some embodiments, the group R is a group represented by formula (L-II). In some embodiments, the group R is a group represented by formula (D-II). In some embodiments, the group R is selected from the group consisting of a group represented by formula (LI), a group represented by formula (DI), a group represented by formula (L-II), and a group represented by formula (D-II). [ka]

[0046] In some embodiments, the compound represented by Formula (I') is a compound represented by Formula (L-I') or a compound represented by Formula (D-I'). In some embodiments, the compound represented by Formula (II') is a compound represented by Formula (L-II') or a compound represented by Formula (D-II). In some embodiments, the compound represented by Formula (I') is a compound represented by Formula (L-I'). In some embodiments, the compound represented by Formula (I') is a compound represented by Formula (D-I'). In some embodiments, the compound represented by Formula (II') is a compound represented by Formula (L-II'). In some embodiments, the compound represented by Formula (II') is a compound represented by Formula (D-II). In some embodiments, the group represented by Formula (I'') is a group represented by Formula (L-I'') or a group represented by Formula (D-I''). In some embodiments, the group represented by Formula (II'') is a group represented by Formula (L-II'') or a group represented by Formula (D-II). In some embodiments, the group represented by Formula (I'') is a group represented by Formula (L-I''). In some embodiments, the group represented by formula (I") is a group represented by formula (D-I"). In some embodiments, the group represented by formula (II") is a group represented by formula (L-II"). In some embodiments, the group represented by formula (II") is a 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 group represented by formula (IIIa), Q4 is -H or -F, and Q5 is -H or -F. [ka] Formula (IIIa).

[0052] In some embodiments, R3 is a group represented by Formula (I), x is 3, R4 is a group represented by Formula (IIIa), Q4 is H, and Q5 is H. In some embodiments, R3 is a group represented by Formula (I), x is 3, R4 is a group represented by Formula (IIIa), Q4 is F, and Q5 is H. In some embodiments, R3 is a group represented by Formula (I), 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 (I), x is 3, R4 is a group represented by Formula (IIIa), Q4 is F, 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 H, 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 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, Q4 is -H or -F, and / or Q5 is -H or -F.

[0054] In some embodiments, the compounds of the present invention are chelated to a radionuclide. In some embodiments, the radionuclide is 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 In some embodiments, the radionuclide comprises or consists of at least one selected from the group consisting of: Ac 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 In some embodiments, the radionuclide comprises or consists of at least one selected from the group consisting of: Ac 68 Ga and 177 In some embodiments, the radionuclide comprises or consists of at least one selected from the group consisting of Lu. 68 In some embodiments, the radionuclide comprises Ga. 177 Contains Lu.

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

[0056] In some embodiments, obtaining the first compound comprises reacting the R2 cyclic peptide with bicyclo[6.1.0]nonyne (BCN)-L2-N-hydroxysuccinimide (NHS) to obtain the first compound. In some embodiments, obtaining the second compound comprises reacting the R1 cyclic peptide, a linear peptide with or without a protecting group, L1-CH2CH2OH with or without a protecting group, or a lysine with or without a protecting group, with DO3AtBu-N3 to obtain the second compound. In some embodiments, the treatment is radiation therapy.

[0057] In some embodiments, the present invention has developed new albumin binders that can significantly increase tumor uptake, have no adverse effects on non-tumor organs, and improve the therapeutic index.

[0058] In order to further explain the technical means and effects adopted by the present invention to achieve the desired objectives, the following detailed description will be given of specific embodiments, structures, features and effects of the present invention with reference to the drawings and preferred examples.

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

[0060] [Table 1]

[0061] The sequences of SEQ ID NOs: 1-6 above are shown in Table 2.

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

[0063] Preparation of Example Compounds The following is an example, but not limited to, of the compound of Example L11. As will be understood by those skilled in the art, the compounds of other Examples (including, but not limited to, the compounds of Examples shown in Table 1) can be synthesized by methods similar to the synthesis of the compound of Example L11 below.

[0064] In this specification, Example L11 can be abbreviated as "L11." Other Examples are similar.

[0065] 1. Preparation of 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) had been dissolved.

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

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

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

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

[0070] 2. Preparation of precursor R1-L1-Lys-DOTA-N3 2.1. The linear peptide Lys(Dde)-D-Phe-Asp(Otbu)-Gly-Arg(Pbf) (i.e., a linear peptide of the protected SEQ ID NO: 1 cyclic peptide) was synthesized by solid-phase synthesis, with the polypeptide chain remaining attached 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 Fmoc protecting group of the last 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 with a solution of 30% trifluoroethanol in dichloromethane for 2 hours. After filtration, the solvent was removed using a rotary evaporator to obtain the product with a protected group.

[0075] 2.6 The product from the previous step was dissolved in dichloromethane and reacted with a 2-fold excess of benzotriazol-1-yl-oxytripyrrolidinylphosphonium hexafluorophosphate (PyBop) and a 10-fold excess of DIEA under reflux at 45°C overnight. The solvent was removed by rotary evaporation to give the cyclized product.

[0076] 2.7, 95% TFA solubility was used to remove the protecting groups in the product structure of the previous step.

[0077] 2.8. The solution was purged with nitrogen to dry it 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 to dryness at room temperature.

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

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

[0080] 2.11, measured by electrospray mass spectrometry: m / z [M+H] + =1434.96(Chemical formula:C 62 H 103 N 19 O 20 The calculated molecular weight is 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 precursor R1-L1-Lys(-R3-H)-DOTA-N3 3.1, 20 mg (13.94 μmol) of R1-L1-Lys-DOTA-N3 was weighed and dissolved in 100 μL of DMF.

[0082] 3.2, 23 μL of DIEA (139.4 μmol) and 11.5 mg of the compound of formula (I′) in which the —N*H 2 group was protected with Boc (20.89 μmol) were added sequentially 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 of the previous step was precipitated using cold ethyl ether.

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

[0086] 3.6. The solution was purged with nitrogen to dry it 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 to dryness at room temperature.

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

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

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

[0090] 4. Preparation of 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. Product separation: High performance liquid chromatography was used. The stationary phase was a semi-preparative C18 column, and the mobile phase was gradient elution, from 5% acetonitrile to 50% acetonitrile in 20 minutes at a flow rate of 4 mL / min.

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

[0094] 4.5, measured by electrospray mass spectrometry: m / z [M+2H] + =1404.47(Chemical formula:C 125 H 201 N 33 O 40 The calculated molecular weight is 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 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: 1M TFA aqueous solution was added to the reaction mixture, and the pH of the reaction solution was adjusted to 5.0-6.0.

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

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

[0101] 5.7, measured by electrospray mass spectrometry: m / z [M+2H] +=1510.58(Chemical formula:C 136 H 210 F3N 33 O 41 The calculated molecular weight is 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 this experiment, the stability of Example L11 compound (1.0 μg / mL) in mouse plasma or PBS was investigated using an in vitro incubation method at constant temperature (37°C). Example L11 compound was dissolved in 1 mL of mouse serum and incubated in vitro for 0 h, 0.5 h, 1 h, 4 h, 24 h, and 48 h, after which the percentage of drug remaining was measured. PBS was used as a negative control. The peak areas of the drug and internal standard were measured using LC-MS / MS, and the ratio was used to calculate the drug concentration.

[0103] The results are shown in Table 3.

[0104] Table 3: Percentage drug remaining after in vitro incubation in mouse plasma or PBS for Example L11 compound [Table 3]

[0105] As can be seen from the above table, the residual drug percentage of the compound of Example L11 after in vitro incubation at constant temperature in mouse plasma or PBS was maintained at 95% or more, indicating high stability.

[0106] Animal experiments 1. Construction of a human pancreatic cancer xenograft tumor model BxPC3 human pancreatic cancer cells were placed in 200 μL of a mixture of phosphate buffer and matrix gel (v / v, 1 / 1) at a concentration of 2 × 10 6100 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, tumors reached approximately 10 mm in diameter, which was already large enough for biodistribution and SPECT / CT imaging studies.

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

[0108] 2.2. Elute the gallium germanium generator with 4 mL of 0.05 M hydrochloric acid solution and rinse. 68 GaCl3 was prepared.

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

[0110] 3. Positron Emission Computed Tomography (PET-CT) of Small Animals PET-CT and image analysis were performed using a small animal NovelMedcal PET-CT scanner (Beijing Yongxin), with a maximum tangential and radial half-width at the center of the field of view of 1.5 mm and a maximum tangential and radial half-width at the edge of the field of view of 1.8 mm.

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

[0112] PET and CT images were acquired using NMSoft workstation software (Beijing Yongxin). Data are presented as a percentage of the injected dose per gram of tissue or organ (ID / g), determined by decay correction for each sample (normalized to a known weight representing the injected dose). Normalization was performed during statistics, and normalized uptake values ​​(SUVs) were calculated using the following formula: SUV=([Bq / mL]×[Animal weight (g)] / [Injection amount (Bq)]) The uptake of the five conjugates into tumor, muscle, and kidney at each time point is shown in Figures 6 and 7.

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

[0114] After injection of the other four conjugates, signals were detected in the systemic blood of mice within a short time, demonstrating that the albumin-binding fragment in the conjugates increased the circulation time of the conjugates. Furthermore, with increasing time, most of the conjugates were excreted in the urine via the kidneys, and the background signal in normal tissues gradually decreased, while the signal in tumor tissues gradually increased, indicating that the conjugates were specifically concentrated in tumor tissues over time.

[0115] Example L11 compound formed 68 For the Ga-L11 conjugate, 6 hours after injection, the tumor / kidney ratio reached approximately 1.4 and continued to increase, indicating that the Example L11 compound has good stability, targeting, and specificity.

[0116] 68 After injection of Ga-L12 complex, the overall imaging trend was 68 Similar to the Ga-L11 complex, but accumulation in tumor tissue after 5-6 hours 68 This was not as clear as for 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 It was lower than that of the Ga-L11 complex.

[0118] 68 Regarding the Ga-L21 conjugate, the Example L21 conjugate has the same important polypeptide target and albumin-binding fragment in its structure as the Example L21 conjugate, but differs in one linker structure, so the tissue distribution tendency and extent of the two are very similar.

[0119] FIG. 7A shows the biodistribution of one representative animal selected from each complex group 5 hours after drug injection.

[0120] As can be seen from the MIP diagram and the quantification results of the tumor, kidney, and muscle ROI regions, 68 The tumor / kidney and tumor / muscle ratios of the Ga-L11 conjugate were the highest among the five conjugates. 68 Compared with the Ga-L00 conjugate, the other four conjugates showed significantly improved in vivo stability and tumor tissue accumulation.

[0121] 4. Example L11 Compound 177 Lu label 6 μL of 0.5 nmol / μL Example L11 compound solution was added to 1 mCi of 177LuCl 3 , 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 radio-high performance liquid chromatography. 177 The Lu-L11 complex can be obtained.

[0123] 5. Small Animal Single Photon Emission Computed Tomography (SPECT-CT) SPECT-CT and image analysis were performed using a small animal NovelMedcal SPECT-CT scanner (Beijing Yongxin). The maximum tangential and radial half-widths at the center of the field of view were 1.5 mm, and the maximum tangential and radial half-widths at the edge of the field of view were 1.8 mm.

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

[0125] The SPECT-CT imaging results are shown in Figure 8. 177 Within 4 days after intravenous injection of Lu-L11 solution, the emission signal could be continuously detected in the mouse tumor tissue, and the signal disappeared in other tissues and organs. This indicates that the compound of Example L11 has good in vivo stability and targeting properties, and is a therapeutic nuclide with a long half-life. 177 These results suggest that it may be useful in combination with Lu for tumor radiotherapy.

[0126] 6. Biodistribution Studies Example 177 Lu-L11, 177 Lu-L12, 177 Lu-D-L11, 177 The 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 then dissected to extract samples.

[0127] Tissues and organs of interest were harvested, weighted and radioactively counted using a gamma counter.

[0128] Figure 9 shows 177 Lu-L11, 177 Lu-L12, 177 Lu-D-L11, 177 Radioactivity distribution in various mouse tissues 24 hours after intravenous injection of four Lu-L11-1 conjugates is shown, where the values ​​on the vertical axis are given as a percentage of the injected dose per gram of tissue or organ (ID / g) and are determined by decay correction for each sample (normalized to a known weight representing the injected dose).

[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 were concentrated in tumors, among which: 177 The concentration of Lu-L12 was higher than that of the other three complexes. These complexes were also concentrated to some extent in the kidney, but were less concentrated in the spleen and uterus.

[0130] 7.Statistical analysis Statistical analysis was performed by two-tailed unpaired t-test in graphpad 6. Probability (p) values ​​less than 0.05 were considered statistically significant.

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

Claims

1. A compound comprising the structure of the following formula (A): 【Chemistry 1】 (In the formula, Said Z １ Ha-L １ R １ or -H, and said Z ２ Ha-L ２ R ２ or -H, and the condition is １ Ga-L １ R １ and / or said Z ２ Ga-L ２ R ２ It is to be Said L １ Ha-(PEG) ｍ -, wherein m is an integer selected from 4 to 30; Said L ２ Ha-(PEG) ｎ -, wherein n is an integer selected from 4 to 30; The R １ comprises a peptide in which arginine, glycine or sarcosine, and aspartic acid are sequentially linked, The R ２ comprises a peptide in which asparagine, glycine or sarcosine, cysteine, and arginine are sequentially linked, The R ３ is a group represented by the following formula (I) or a group represented by the following formula (II), 【Chemistry 2】 The R ４ is a group represented by formula (III), a group represented by formula (IV), or a long-chain fatty acid, 【Transformation 3】 Q １ , the Q ２ , the Q ３ , the Q ４ , and the Q ５ are each independently —H, —F, —Cl, —Br, —I, or —C １ -C ６ Linear or branched alkyl, C １ -C ６ Linear or branched fluoroalkyl, and C １ -C ６ selected from the group consisting of linear or branched fluoroalkoxy; wherein x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; wherein y is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6.

2. Said Z １ Ha-L １ R １ and said Z ２ Ha-L ２ R ２ and / or wherein m is 4; and / or The compound of claim 1, wherein n is 4.

3. said x is 3, and / or The R ４ The compound according to claim 1 or 2, wherein: is a group represented by formula (III), and y is 2 or 3.

4. The R ４ is a group represented by formula (III), Q １ is —H, and said Q ２ is —H, and said Q ３ is -H, -F, -Cl, -Br, -I, -CH ２ F, -CHF ２ and -CF ３ wherein Q is selected from the group consisting of ４ is -H or -F, and / or said Q ５ is —H or —F, Optionally, the Q １ is —H, and said Q ２ is —H, and said Q ３ Ha-CF ３ and Q ４ is -H or -F, and / or said Q ５ is —H or —F, Optionally, the Q １ is —H, and said Q ２ is —H, and said Q ３ Ha-CF ３ and Q ４ is —H or —F, and said Q ５ The compound according to any one of claims 1 to 3, characterized in that is -H or -F.

5. The R １ is a cyclic peptide and further comprises lysine; Optionally, the R １ is a cyclic peptide containing L-lysine and a tripeptide sequence in which L-arginine, glycine or sarcosine, and L-aspartic acid are sequentially linked, Optionally, the R １ is a cyclic peptide consisting of 4 to 7 amino acids, Optionally, the R １ is a cyclic peptide consisting of five amino acids, Optionally, the R １ is a cyclic peptide as set forth in SEQ ID NO: 1 or 2, and / or The R ２ is a cyclic peptide and further comprises lysine; Optionally, the R ２ is a cyclic peptide containing L-lysine and a tripeptide sequence in which L-asparagine, glycine or sarcosine, and L-arginine are sequentially bound, Optionally, the R ２ is a cyclic peptide consisting of 4 to 7 amino acids, Optionally, the R ２ is a cyclic peptide consisting of 5 or 6 amino acids, Optionally, the R ２ The compound according to any one of claims 1 to 4, wherein said compound is a cyclic peptide represented by any one of SEQ ID NOs: 3 to 6.

6. 10. Use of a compound according to any one of claims 1 to 5 in the preparation of a radionuclide label or radionuclide labelled reagent.

7. A compound according to any one of claims 1 to 3; a radionuclide chelated to said compound; A radionuclide formulation comprising:

8. The radionuclide is ４４ Sc, ４７ Sc, ６２ Cu, ６４ Cu, ６７ Cu, 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 Ac, Optionally, 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 Ac, Optionally, the radionuclide is ６８ Ga or １７７ 8. The radionuclide preparation according to claim 7, characterized in that it contains Lu.

9. 9. A method for preparing a compound according to any one of claims 1 to 6 or a radionuclide formulation according to claim 7 or 8, comprising the steps of: Obtaining a first compound having a structure represented by the following formula (A1): 【Chemistry 4】 Obtaining a second compound having a structure represented by the following formula (A2): 【Transformation 5】 -N*H of the second compound ２ and a compound represented by the following formula (I') or a compound represented by the following formula (II') or -N*H thereof. ２ forming an amide bond with the —C*OOH group of the compound in which the group is protected to obtain a third compound having a group represented by the following formula (I″) or a group represented by the following formula (II″); 【Transformation 6】 reacting the third compound with the first compound to obtain a fourth compound; The fourth compound is a group represented by formula (I″) or a group represented by formula (II″) —N*H ２ forming an amide bond between the group and the —C*OOH group of a compound represented by the following formula (III′); 【Transformation 7】 A preparation method comprising:

10. 10. Use of a compound according to any one of claims 1 to 5, or a radionuclide formulation according to claim 7 or 8, in the preparation of a medicament for use in the detection of cancer, the diagnosis of cancer, the monitoring of cancer progression, the monitoring of cancer treatment or the treatment of cancer.

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