Novel heterodimer molecule for tumor radioactive therapy

Abstract

The invention discloses a novel heterodimer molecule for tumor radioactive therapy. Specifically, the invention discloses a compound or a pharmaceutically acceptable salt thereof. The compound or the pharmaceutically acceptable salt comprises a structure as shown in an attached drawing of the abstract or consists of the structure as shown in the attached drawing of the abstract. The invention also discloses application of the compound in radionuclide labeling or preparation of a radionuclide labeling reagent. Also disclosed is a radionuclide formulation comprising a radionuclide chelated therewith. Also disclosed are uses thereof in the preparation of medicaments for detecting cancer, diagnosing cancer, monitoring cancer progression, monitoring cancer therapy or treating cancer.

Description

Technical Field

[0001] The present application relates to the field of molecular imaging, and more particularly to a novel heterodimer molecule for tumor radiotherapy. Background Art

[0002] Integrin α v β3 Receptor and Tumor Neoangiogenesis

[0003] Angiogenesis is the process of forming new blood vessels from existing blood vessels, which is widely considered to be an important way to ensure that rapidly growing tumor tissues take up nutrients and oxygen. At the same time, there is also an important association with the invasion and metastasis of tumor cells. Since the growth and metastasis of tumors highly depend on angiogenesis, this phenomenon is considered to be a major target for tumor diagnosis and treatment. The process of tumor angiogenesis is stimulated by a variety of growth factors, including integrin α v β3 receptor and CD13 receptor.

[0004] Integrin α v β3 plays an important role in tumor angiogenesis and is a receptor for extracellular matrix proteins with the RGD tripeptide sequence. These include vitronectin, fibronectin, fibrinogen, collagen, von Willebrand factor, osteopontin, and adenovirus particles. Integrin α v β3 is expressed at low levels in epithelial cells and mature endothelial cells, but is overexpressed in activated endothelial cells of tumor neoangiogenesis and some tumor cells. Research shows that integrin α v β3 is highly correlated with the processes of tumor growth, invasion, and metastasis, and is a key molecular target for the early detection and treatment of rapidly growing solid tumors.

[0005] Albumin Carrier Strategy

[0006] Albumin has been widely explored as a drug carrier due to its high biocompatibility, strong non-antigenicity, good biodegradability, and easy surface modification. So far, several albumin-based nano-delivery systems have been successfully transformed into clinical drugs, significantly improving the pharmacokinetics and tumor accumulation of drugs, thereby enhancing the therapeutic efficiency of drugs and reducing side effects.

[0007] In the field of tumor radiotherapy, through molecular design, albumin-binding fragments can be introduced into carrier molecules, so that in vivo, the targeted molecules labeled with radioactive isotopes can bind to albumin, and their blood circulation time and half-life can be significantly extended, and the pharmacokinetic properties can also be improved. At the same time, the large particle size of albumin and the EPR effect of tumor tissues can be used to increase the targeting of targeted probes and radioactive isotopes, and because the tumor tissue environment has a high metabolic level and a high uptake rate of nutrients such as albumin, the tumor uptake rate of targeted probes and radioactive isotopes can be increased.

[0008] However, the use of the above albumin loading technology also leads to an increase in the absorption of radioactive targeting peptides by healthy organs, thereby producing corresponding side effects. Therefore, it is necessary to develop a new albumin binder that can significantly increase tumor absorption without having a negative impact on non-tumor organs, thereby improving the therapeutic index. SUMMARY OF THE INVENTION

[0009] In some embodiments, there is provided a compound or a pharmaceutically acceptable salt thereof, comprising or consisting of part of formula (A).

[0010]

[0011] Wherein, R1 and R2 each comprise a peptide sequence in which arginine, glycine or sarcosine, and aspartic acid are sequentially linked; Z is part of formula (A1), part of formula (A2), or a long-chain fatty acid, wherein Q1, Q2, Q3, Q4, and Q5 are each independently selected from the group consisting of -H, -F, -Cl, -Br, -I, -SF3, -SF2Cl, -SF5, -SF4Cl, C1–C6 straight-chain or branched-chain alkyl, C1–C6 straight-chain or branched-chain fluoroalkyl, and C1–C6 straight-chain or branched-chain fluoroalkoxy; m is an integer selected from between 4 and 30; n is an integer selected from between 4 and 30; x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; y is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6; and z is 0 or 1.

[0012]

[0013] In some embodiments, the present application provides a radionuclide preparation, comprising or consisting of the compound of the present application or a pharmaceutically acceptable salt thereof, and a radionuclide chelated therewith.

[0014] In some embodiments, the present application provides a method for preparing the compound of the present application or a pharmaceutically acceptable salt thereof, or a radionuclide preparation, comprising: contacting a compound of formula (1) or a protected derivative thereof with a compound of formula (2) or a protected derivative thereof to obtain a compound of formula (3); contacting the compound of formula (3) or a protected derivative thereof with a compound of formula (4) or a protected derivative thereof to obtain a compound of formula (5); and contacting the compound of formula (5) or a protected derivative thereof with a compound of formula (6) or a protected derivative thereof to obtain a compound of formula (A).

[0015]

[0016]

[0017] In some embodiments, the present application provides the use of the compounds of the present application or their pharmaceutically acceptable salts, or radionuclide preparations, in the preparation of drugs for detecting cancer, diagnosing cancer, monitoring cancer progression, monitoring cancer treatment, or treating cancer. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 Is the electrospray mass spectrum of the compound of formula (4).

[0019] Figure 2 Is the electrospray mass spectrum of the compound of formula (3).

[0020] Figure 3 Is the electrospray mass spectrum of the compound of formula (5).

[0021] Figure 4 Is 68 The radiochromatogram of the Ga-L41 complex ( 68 The Ga-compound of formula (B) complex).

[0022] Figure 5 Is 68 The standardized uptake values of the Ga-L41 complex in tumors, heart, muscle, and kidneys at each time point.

[0023] Figure 6 Is 68 The ratios of the standardized uptake values between tumors and heart, kidneys, and muscles of the Ga-L41 complex at each time point.

[0024] Figure 7 Is 68 The uptake values of the Ga-L41 complex in each major organ tissue at each time point, and the uptake after blocking.

[0025] Figure 8 Is of formula (A). DETAILED DESCRIPTION

[0026] Terms and Definitions

[0027] As used herein, the singular terms refer to one or more than one. For example, "element" or "an element" both refer to one element or more than one element. As used herein, "a plurality" means at least two.

[0028] As used herein, the term "about" refers to approximation, within the range of approximately or near. When the term "about" is used in connection with a numerical range, it modifies the range by extending the boundaries above or below the given numerical value. Generally speaking, the term "about" as used herein causes a numerical value to vary up or down by 10% from the given value. In one aspect, the term "about" refers to plus or minus 20% of the numerical value of the number it modifies. For example, "about 50%" refers to the range of 45% - 55%. Numerical ranges recited herein by endpoints include all integers and fractions subsumed within that 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 are considered to be modified by the term "about".

[0029] As used herein, "comprising" or "including" is intended to mean that the compositions (such as devices, compositions, or methods, etc.) include the recited elements (such as each unit of the device, each component of the composition, or the substantial steps of the method, etc.), but do not exclude other elements. When used to define compositions and methods, "consisting essentially of" means excluding other elements that are of any significance for the stated purpose. Thus, a composition consisting essentially of the elements defined herein does not exclude other elements that do not substantially affect the basic and novel features of the claimed invention. "Consisting of" means excluding other elements of the combination (unit components and substantial method steps). Embodiments defined by each of these transitional terms are within the scope of the present invention.

[0030] As used herein, the term "and / or" refers to and encompasses any and all possible combinations of one or more of the 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 can be included alone, or any combination of two or more of the listed items can be included. For example, if a group, combination, or composition, etc., is described as including (or comprising) components A, B, C, and / or D, then the composition can include A alone; include B alone; include C alone; include D alone; include a combination of A and B; include a combination of A and C; include a combination of A and D; include a combination of B and C; include a combination of B and D; include a combination of C and D; include a combination of A, B, and C; include a combination of A, B, and D; include a combination of A, C, and D; include a combination of B, C, and D; or include a combination of A, B, C, and D.

[0031] The term "amino acid" may be used interchangeably with "amino acid residue" and may refer to free amino acids and amino acid residues of peptides. It will be clear from the context in which the term is used whether it refers to a free amino acid or a residue of a peptide. As used herein, "amino acid" is intended to include natural and synthetic amino acids and includes D- and L-amino acids. "Standard amino acid" refers to any of the twenty standard L-amino acids (including glycine) commonly found in naturally occurring peptides. As used herein, "D-form" and "L-form" amino acids, unless otherwise indicated, are not intended to exclude amino acids that do not have chirality, such as glycine. "Non-standard amino acid residue" refers to any amino acid other than a standard amino acid, whether prepared synthetically or derived from natural sources. As used herein, "synthetic amino acid" also includes chemically modified amino acids, including but not limited to salts, amino acid derivatives (such as amides) and substituents. The amino acids contained in the peptides of the present invention can be modified by methylation, amidation, acetylation or substitution with other chemical groups that can alter the circulatory half-life of the peptide without detrimentally affecting its activity, and particularly the amino acids located at the C-terminus or N-terminus. Disulfide bonds may or may not be present in the peptides of the present invention.

[0032] In the peptides described herein that are sequentially linked by a plurality of amino acids, the order from the N-terminus to the C-terminus corresponds to the order of the written description from the front to the back; for example, the amino acid first described is located at the N-terminus of the peptide, and the amino acid last described is located at the C-terminus of the peptide.

[0033] As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one active ingredient, which is acceptable for studying specific, effective results in mammals (such as but not limited to humans). Based on the needs of those skilled in the art, those of ordinary skill in the art will understand and know the techniques suitable for determining whether the active ingredient has the desired effective effect.

[0034] As used herein, the term "pharmaceutically acceptable salt" refers to a salt derived from a compound of the present invention that retains the biological effectiveness and properties of the compound of the present invention and is generally not a biologically or otherwise undesirable salt. Due to the presence of amino and / or carboxyl groups or groups similar thereto, the compounds of the present invention are capable of forming acid salts and / or base salts. The term "pharmaceutically acceptable salt" may refer to pharmaceutically acceptable addition salts prepared from pharmaceutically acceptable non-toxic acids or bases (including inorganic acids and bases and organic acids and bases).

[0035] As used herein, "polypeptide" refers to a polymer composed of amino acid residues, their related naturally occurring structural variants and synthetic non-naturally occurring analogs linked by peptide bonds, their related naturally occurring structural variants and synthetic non-naturally occurring analogs.

[0036] As described herein, a "polynucleotide" refers to a single-stranded or parallel and antiparallel strands of nucleic acid. Thus, a polynucleotide can be a single-stranded or double-stranded nucleic acid.

[0037] As described herein, the compounds or ions of the present application include a plurality of variable groups. Those of ordinary skill in the art should recognize that the combinations of groups contemplated by the present application are combinations of chemically permissible compounds or ions.

[0038] As described herein, the stereochemistry of a chiral center can be defined according to the convention of those skilled in the art, i.e., using a solid wedged bond to indicate a group that points out of the plane of the paper (towards the reader) and using a hashed bond to indicate a group that points into the plane of the paper (away from the reader). If such a representation is used, then it can be understood that a specific single stereoisomer of the groups shown in each chemical structure herein is indicated. Any bond in this article that is not specifically represented by a solid wedged bond or a hashed bond should be considered as not specifically indicating whether the bond points out of the plane of the paper, into the plane of the paper, or lies in the plane of the paper, but does not prevent it from pointing out of the plane of the paper or into the plane of the paper when chemically permissible. A bond represented by a wavy bond in this article should be considered as simultaneously disclosing an alternative technical solution of a solid wedged bond and a hashed bond.

[0039] As described herein, the term "isomer" means a compound having the same molecular formula but different in the nature or order of bonding of its atoms or the arrangement of its atoms in space. Among them, the term "stereoisomer" means an isomer in which the arrangement of atoms in space is different; the term "enantiomer" means a stereoisomer with one or more asymmetric centers, which are non-superimposable mirror images of each other; the term "diastereomer" means a stereoisomer that is not an enantiomer and has 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, there can be a pair of enantiomers. Enantiomers can be characterized by the absolute configuration of one or more of their asymmetric centers and designated as the R-configuration or S-configuration, or designated as dextrorotatory or levorotatory in terms of the way the molecule rotates the plane of polarized light. Chiral compounds can exist as individual enantiomers or as mixtures thereof, such as racemic mixtures. The compounds of the present application may contain asymmetric or chiral centers and thus exist in different stereoisomeric forms. All stereoisomers of the compounds of the present application, including but not limited to diastereomers, enantiomers, and atropisomers, and mixtures thereof such as racemic mixtures, are considered to form part of the present application.

[0040] The term "protected derivative" means a derivative of a compound (such as a compound specified herein), in which one or more functional groups of the compound (such as functional groups specified herein) are protected or blocked to avoid undesired reactions. Functional groups that can be protected are, for example, carboxylic acid groups, amino groups, hydroxyl groups, thiol groups, carbonyl groups, etc., but are not limited thereto. Representative protecting groups for carboxyl groups are, for example, esters (such as p-methoxybenzyl ester), amides, and hydrazides, but are not limited thereto; representative protecting groups for amino groups are, for example, carbamates (such as tert-butoxycarbonyl) and amides, but are not limited thereto; representative protecting groups for hydroxyl groups are, for example, ethers and esters, but are not limited thereto; representative protecting groups for thiol groups are, for example, thioethers and thioesters, but are not limited thereto; representative protecting groups for carbonyl groups are, for example, acetals and ketals, but are not limited thereto.

[0041] As described herein, especially the atoms shown in the structural formulas herein should be considered to include each isotope of the atom. For example, the hydrogen atom (H) shown either in words or in the structural formula or omitted herein should be considered to include each isotope of hydrogen, such as, but not limited to, protium, deuterium, tritium, etc.; the carbon atom (C) shown either in words or in the structural formula herein should be considered to include each isotope of carbon, such as, but not limited to 12 C, 13 C, 14 C, etc.

[0042] The expression "(PEG) n " herein means polyethylene glycol composed of n ethylene glycol monomers. Similarly, the expression "(PEG) m " herein means polyethylene glycol composed of m ethylene glycol monomers. For example, the expression "(PEG)4" herein means polyethylene glycol composed of 4 ethylene glycol monomers.

[0043] Embodiment

[0044] In some embodiments, R1 or R2 comprises a tripeptide sequence sequentially linked by arginine, glycine or sarcosine, and aspartic acid. In some embodiments, R1 or R2 comprises a tripeptide sequence sequentially linked by L-arginine, glycine or sarcosine, and L-aspartic acid. In some embodiments, R1 or R2 comprises a tripeptide sequence sequentially linked by L-arginine, glycine, and L-aspartic acid. In some embodiments, R1 or R2 comprises a tripeptide sequence sequentially linked by L-arginine, sarcosine, and L-aspartic acid. In some embodiments, R1 or R2 is a cyclic peptide. In some embodiments, R1 or R2 are each independently selected from cyclic peptides consisting of 4 to 7 amino acids. In some embodiments, R1 or R2 is a cyclic peptide consisting of 5 amino acids. In some embodiments, R1 or R2 further comprises lysine. In some embodiments, R1 or R2 is a cyclic peptide comprising lysine. In some embodiments, R1 or R 22 are each independently selected from cyclic peptides consisting of 4 to 7 amino acids comprising lysine. In some embodiments, R1 or R2 is a cyclic peptide consisting of 5 amino acids comprising lysine. In some embodiments, R1 or R2 is the cyclic peptide shown in SEQ ID NO:1 or SEQ ID NO:2. In some embodiments, R1 or R2 is the cyclic peptide shown in SEQ ID NO:1. In some embodiments, R1 or R2 is the cyclic peptide shown in SEQ ID NO:2. In some embodiments, R1 is the cyclic peptide shown in SEQ ID NO:1, and R2 is the cyclic peptide shown in SEQ ID NO:1. In some embodiments, R1 is the cyclic peptide shown in SEQ ID NO:2, and R2 is the cyclic peptide shown in SEQ ID NO:2. In some embodiments, R1 is the cyclic peptide shown in SEQ ID NO:1, and R2 is the cyclic peptide shown in SEQ IDNO:2. In some embodiments, R1 is the cyclic peptide shown in SEQ ID NO:2, and R2 is the cyclic peptide shown in SEQ ID NO:1. In some embodiments, R1 and R2 are the same group.

[0045] In some embodiments, Z is a moiety of formula (A1), a moiety of formula (A2), or a long-chain fatty acid. In some embodiments, Z is a moiety of formula (A1). In some embodiments, Z is a moiety of formula (A2). In some embodiments, Z is a long-chain fatty acid.

[0046] In some embodiments, Q1, Q2, Q3, Q4, and Q5 are each independently selected from the group consisting of -H, -F, -Cl, -Br, -I, -SF3, -SF2Cl, -SF5, -SF4Cl, C1–C6 straight or branched chain alkyl, C1–C6 straight or branched chain fluoroalkyl, and C1–C6 straight or branched chain fluoroalkoxy. In some embodiments, Z is a moiety of formula (A1), and Q1, Q2, Q3, Q4, and Q5 are each independently selected from the group consisting of -H, -F, -Cl, -Br, -I, -SF3, -SF2Cl, -SF5, -SF4Cl, C1–C6 straight or branched chain alkyl, C1–C6 straight or branched chain fluoroalkyl, and C1–C6 straight or branched chain fluoroalkoxy. 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. In some embodiments, Z is a moiety of formula (A1), wherein Q1 is -H; and / or Q2 is -H; and / or Q3 is selected from the group consisting of -H, -F, -Cl, -Br, -I, -CH2F, -CHF2, and -CF3; and / or Q4 is -H or -F; and / or Q5 is -H or -F. In some embodiments, Q1 is H, Q2 is H, Q3 is -Br, Q4 is H, and Q5 is H.

[0047] In some embodiments, m is an integer selected from between 4 and 30. In some embodiments, m is an integer selected from between 4 and 25. In some embodiments, m is an integer selected from between 4 and 20. In some embodiments, m is an integer selected from between 4 and 15. In some embodiments, m is an integer selected from between 4 and 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.

[0048] In some embodiments, n is an integer selected from between 4 and 30. In some embodiments, n is an integer selected from between 4 and 25. In some embodiments, n is an integer selected from between 4 and 20. In some embodiments, n is an integer selected from between 4 and 15. In some embodiments, n is an integer selected from between 4 and 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.

[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, z is 0. In some embodiments, z is 1.

[0052] In some embodiments, in Formula (A), Formula (3), or Formula (5), the moiety is In some embodiments, in Formula (A), Formula (3), or Formula (5), the moiety is

[0053] In some embodiments, R1 is the cyclic peptide shown in SEQ ID NO:1, R2 is the cyclic peptide shown in SEQ ID NO:1; Z is the moiety of Formula (A1), Q1 is H, Q2 is H, Q3 is -Br, Q4 is H, Q5 is H; m is 4; n is 4; x is 3; y is 3; z is 1; and in Formula (A), Formula (3), or Formula (5), the moiety is

[0054] In some embodiments, m is 4; and / or n is 4; and / or x is 3; and / or y is 3; and / or the z is 1; and / or in Formula (A), the moiety is

[0055] In some embodiments, the compound is a compound of Formula (B),

[0056]

[0057] In some embodiments, the compound or a pharmaceutically acceptable salt thereof of the present application chelates a radionuclide. In some embodiments, the radionuclide includes those selected from 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, or at least one selected from the group consisting of or consisting of. In some embodiments, the radionuclide comprises a selected from the group consisting of 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, 211A t, 223 Ra, and 225 Ac, or at least one selected from the group consisting of or consisting of. In some embodiments, the radionuclide comprises a selected from the group consisting of 68 Ga and 177 Lu, or at least one selected from the group consisting of or consisting of. In some embodiments, the radionuclide comprises 68 Ga. In some embodiments, the radionuclide comprises 177 Lu.

[0058] In some embodiments, the preparation method of the present application further comprises preparing a compound of formula (4), comprising: reacting a R2 cyclic peptide with bicyclo[6.1.0]nonyne (BCN)–(PEG) n –N-hydroxysuccinimide (NHS).

[0059] In some embodiments, the preparation method of the present application further comprises preparing a compound of formula (1), comprising: a R1 cyclic peptide or its linear peptide or its protected derivative, (PEG) m–CH2CH2OH or a protected derivative thereof, lysine or a protected derivative thereof, and DO3AtBu-N3 react to obtain a second compound.

[0060] In some embodiments, provided is the use of the compounds of the present application in radionuclide labeling. In some embodiments, provided is the use of the compounds of the present application in the preparation of radionuclide-labeled targeting molecules. In some embodiments, provided is the use of the compounds of the present application in the preparation of radionuclide-labeling reagents. In some embodiments, provided is the use of the compounds of the present application in the preparation of drug carriers. In some embodiments, provided is the use of the compounds of the present application as drug carriers. In some embodiments, provided is the use of the compounds or radionuclide preparations of the present application in the preparation of drugs for detecting cancer, diagnosing cancer, monitoring cancer progression, monitoring cancer treatment, or treating cancer. In some embodiments, provided is the use of the compounds or radionuclide preparations of the present application in detecting cancer, diagnosing cancer, monitoring cancer progression, monitoring cancer treatment, or treating cancer.

[0061] In some embodiments, provided is a pharmaceutical composition comprising the compounds of the present application or pharmaceutically acceptable salts thereof. In some embodiments, provided are the compounds or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present application for radionuclide labeling. In some embodiments, provided is a radionuclide-labeled targeting molecule comprising, or consisting of, the compounds of the present application or pharmaceutically acceptable salts thereof. In some embodiments, provided is a radionuclide-labeling reagent comprising, or consisting of, the compounds of the present application or pharmaceutically acceptable salts thereof. In some embodiments, provided is a drug carrier comprising, or consisting of, the compounds of the present application or pharmaceutically acceptable salts thereof. In some embodiments, provided is a preparation for detecting cancer, diagnosing cancer, monitoring cancer progression, monitoring cancer treatment, or treating cancer, comprising the compounds of the present application or pharmaceutically acceptable salts thereof or radionuclide preparations, or consisting of the same. In some embodiments, provided are the compounds or pharmaceutically acceptable salts thereof or radionuclide preparations of the present application for detecting cancer, diagnosing cancer, monitoring cancer progression, monitoring cancer treatment, or treating cancer.

[0062] In some embodiments, a method of radiolabeling is provided, comprising administering the compound that chelates a radionuclide or a pharmaceutically acceptable salt thereof, or the radionuclide preparation. In some embodiments, a method of radiolabeling is provided, comprising contacting the compound that chelates a radionuclide or a pharmaceutically acceptable salt thereof, or the radionuclide preparation, with an object to be radiolabeled with the radionuclide. In some embodiments, a method of detecting cancer, diagnosing cancer, monitoring cancer progression, or monitoring cancer treatment is provided, comprising: administering the compound that chelates a radionuclide or a pharmaceutically acceptable salt thereof, or the radionuclide preparation, to a subject for detecting cancer, diagnosing cancer, monitoring cancer progression, or monitoring cancer treatment; detecting the radionuclide and determining the level and location of the radionuclide in the body of the subject being treated; and comparing the level and location with the level and location of the radionuclide at the same location in an otherwise identical subject who is not affected or in an unaffected area of the subject being treated, wherein a higher level or different location of the radionuclide in the body of the subject being treated as compared to the level and location of the radionuclide in the sample from an otherwise identical subject who is not affected or from an unaffected area of the subject being treated indicates that the subject being treated has cancer, thereby detecting cancer, diagnosing cancer, monitoring cancer progression, or monitoring cancer treatment. In some embodiments, a method of treating cancer in a patient is provided, comprising administering the compound that chelates a radionuclide or a pharmaceutically acceptable salt thereof, or the radionuclide preparation. In some embodiments, a method of treating cancer in a patient is provided, comprising contacting the compound that chelates a radionuclide or a pharmaceutically acceptable salt thereof, or the radionuclide preparation, with the patient.

[0063] In some embodiments, the treatment is radiotherapy. In some embodiments, the cancer is pancreatic cancer.

[0064] In some embodiments, the compounds of the present application provide novel albumin binders that can significantly increase tumor uptake without having a negative impact on non-tumor organs, thereby improving the therapeutic index.

[0065] In some embodiments, the compounds of the present application provide a targeting integrin α v homodimeric radionuclide carrier molecule for β3 receptors. Its structure contains an albumin-binding fragment, an α v β3 targeting polypeptide fragment (SEQ ID NO:1), and a chelator fragment for a radionuclide or ion, and the fragments are covalently linked; the chelator for the radionuclide or ion can be, for example, DOTA, which covalently links two α vThe β3-targeting polypeptide and albumin-binding fragment can be, for example, a structure represented by formula (C) or especially a structure represented by formula (C′), and the spacer of the chelator for a radionuclide or ion can be, for example, –(PEG)4–, and the radionuclide can be 68 Ga,

[0066]

[0067] In some embodiments, the compounds of the present application, especially the compounds of formula (B), show more excellent tumor targeting effects in the BxPC3 xenograft mouse model.

[0068] To further elaborate on the technical means and effects adopted by the present application to achieve the predetermined purpose, the following will, in conjunction with the accompanying drawings and preferred embodiments, elaborate in detail on the specific embodiments, structures, features and their effects according to the present application.

[0069] Example

[0070]

Preparation of Compounds of Formula (A)

[0071] The following takes the compound of formula (B) (R1 is the cyclic peptide shown in SEQ ID NO: 1, R2 is the cyclic peptide shown in SEQ ID NO: 1; Z is the part of formula (A1), Q1 is H, Q2 is H, Q3 is -Br, Q4 is H, Q5 is H; m is 4; n is 4; x is 3; y is 3; z is 1; and the part in formula (A) is ) as an example. Those skilled in the art can further extend on the basis of the synthesis method of the compound of formula (B) disclosed below to obtain the synthesis methods of other embodiments in the compound of formula (A).

[0072] 1. Preparation of Compound of Formula (4) (RGD-(PEG)4-BCN)

[0073] 1.1 Add 46 μL of N,N-diisopropylethylamine (DIEA) (278 μmol) to 100 μL of N,N-dimethylformamide (DMF) dissolved with 16.8 mg of the cyclic peptide of SEQ ID NO: 1 (27.78 μmol) and 22.5 mg of BCN-(PEG)4-NHS ester (41.7 μmol).

[0074] 1.2 Stir the reaction mixture at room temperature for 2 hours.

[0075] 1.3 Separate the product: Use high performance liquid chromatography (HPLC). The stationary phase is a semi-preparative C18 column, the mobile phase adopts gradient elution, the flow rate is 4 mL / min, and it changes from 5% acetonitrile to 50% acetonitrile within 20 minutes.

[0076] 1.4 Identification product: by high performance liquid chromatography and mass spectrometry analysis.

[0077] 1.5 Determination result of electrospray mass spectrometry (ESI-MS): m / z [M+H] + = 1027.55 (chemical formula: C 49 H 74 N 10 O 14 , calculated molecular weight 1026.54). The electrospray mass spectrometry diagram is as Figure 1 , the horizontal axis is the mass-to-charge ratio (m / z), and the vertical axis is the relative intensity (%).

[0078] 2. Preparation of Compound of Formula (1) (RGD-(PEG)4-Lys-DOTA-N3)

[0079] 2.1 Synthesize the linear peptide Lys(Dde)–D-Phe–Asp(Otbu)–Gly–Arg(Pbf) (i.e., the linear peptide of the protected SEQ ID NO:1 cyclic peptide) by solid-phase synthesis method, and keep the polypeptide chain on the resin.

[0080] 2.2 Remove the 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) protecting group of the first lysine side chain with 2% hydrazine hydrate DMF solution.

[0081] 2.3 After washing the resin with DMF, remove the 9-fluorenylmethyl chloroformate (Fmoc) protecting group of the last arginine with 20% piperidine DMF solution.

[0082] 2.4 After washing the resin with DMF, sequentially connect Fmoc-PEG4-CH2CH2OH, Fmoc-Lys(Boc)-OH, and DO3AtBu-N3 by solid-phase synthesis method.

[0083] 2.5 After washing the resin with DMF, cut the resin with 30% trifluoroethanol dichloromethane (DCM) solution for 2 hours. After filtration, dry the solvent with a rotary evaporator to obtain the product with protecting groups.

[0084] 2.6 Dissolve the product of the previous step with DCM, add twice the excess of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (PyBop) and ten times the excess of DIEA, and reflux at 45 °C overnight. After the reaction, remove the solvent with a rotary evaporator to obtain the cyclized product.

[0085] 2.7 Remove the protecting groups in the structure of the product of the previous step with 95% TFA cleavage solution.

[0086] 2.8 Blow dry the cleavage solution as much as possible with nitrogen, precipitate with ether, centrifuge to remove the supernatant, wash the precipitate with ether six times, and then volatilize at room temperature.

[0087] 2.9 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 method at a flow rate of 4 mL / min, changing from 5% acetonitrile to 50% acetonitrile within 20 minutes.

[0088] 2.10 Identification of products: By high performance liquid chromatography and mass spectrometry analysis.

[0089] 3. Preparation of Compound of Formula (3) (RGD-(PEG)4-Lys(-Part of Formula (2))-DOTA-N3)

[0090] 3.1 Weigh 20 mg (13.94 μmol) of the compound of formula (1) and dissolve it in 100 μL of N,N-dimethylformamide (DMF).

[0091] 3.2 Add 23 μL of DIEA (139.4 μmol) and 11.5 mg of the compound of formula (2) with a protected primary amino group Boc (20.89 μmol) to the above solution in sequence.

[0092] 3.3 Stir the reaction mixture at room temperature for 2 hours.

[0093] 3.4 Precipitate the product of the above step with ice-cold ether.

[0094] 3.5 Remove the protecting group on the -R group of the product molecule of the above step with 95% TFA cleavage solution.

[0095] 3.6 Evaporate the cleavage solution to dryness as much as possible with nitrogen, precipitate with ether, centrifuge to remove the supernatant, wash the precipitate six times with ether, and then evaporate to dryness at room temperature.

[0096] 3.7 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 method at a flow rate of 4 mL / min, changing from 5% acetonitrile to 50% acetonitrile within 20 minutes.

[0097] 3.8 Identification of products: By high performance liquid chromatography and mass spectrometry analysis.

[0098] 3.9 Results of electrospray mass spectrometry (ESI-MS): m / z [M+2H] 2+ = 832.25 (chemical formula: C 72 H 119 N 21 O 24 , calculated molecular weight 1661.87). The electrospray mass spectrometry diagram is as Figure 2 , the horizontal axis is the mass-to-charge ratio (m / z), and the vertical axis is the relative intensity (%).

[0099] 4. Preparation of Compound of Formula (5) (R1-(PEG)4-Lys(-Part of Formula (2))-DOTA-click-(PEG)4-R 2 )

[0100] 4.1 Weigh 15 mg (9 μmol) of the compound of formula (3) and 13.5 mg (13.14 μmol) of the compound of formula (4) separately, and dissolve them in 100 μL of N,N-dimethylformamide (DMF).

[0101] 4.2 Stir the reaction mixture at room temperature for 2 hours.

[0102] 4.3 Separate the product: Use high performance liquid chromatography (HPLC). The stationary phase is a semi-preparative C18 column, the mobile phase uses gradient elution, the flow rate is 4 mL / min, and it changes from 5% acetonitrile to 50% acetonitrile within 20 minutes.

[0103] 4.4 Identify the product: By high performance liquid chromatography and mass spectrometry analysis.

[0104] 4.5 Results of electrospray mass spectrometry (ESI-MS): m / z [M+2H] 2+ = 1346.11 (chemical formula: C 121 H 193 N 31 O 38 , calculated molecular weight 2688.40). The electrospray mass spectrum is as shown in Figure 3 , the horizontal axis is the mass-to-charge ratio (m / z), and the vertical axis is the relative intensity (%).

[0105] 5. Preparation of Compound of Formula (A) (Compound of Formula (B), R1-(PEG)4-Lys(-Part of Formula (2)-Part of Formula (6))- DOTA-click-(PEG)4-R2)

[0106] 5.1 Weigh 12 mg (4.46 μmol) of the compound of formula (5), and dissolve it in 100 μL of N,N-dimethylformamide (DMF).

[0107] 5.2 Add 7 μL of DIEA (42.8 μmol) and 5.6 mg of the compound of formula (6) (17 μmol) to the above solution in sequence.

[0108] 5.3 Stir the reaction mixture at room temperature for 2 hours.

[0109] 5.4 Add 1 M aqueous TFA solution to the reaction mixture to adjust the pH of the reaction solution to 5.0 - 6.0.

[0110] 5.5 Separate the product: Use high performance liquid chromatography (HPLC). The stationary phase is a semi-preparative C18 column, the mobile phase uses gradient elution, the flow rate is 4 mL / min, and it changes from 20% acetonitrile to 32% acetonitrile within 20 minutes.

[0111] 5.6 Identify the product: By high performance liquid chromatography and mass spectrometry analysis.

[0112]

Animal Experiment

[0113] 1. Construction of Human Pancreatic Cancer Xenograft Model

[0114] BxPC3 human pancreatic cancer cells were taken and implanted with 5×10 6 cells subcutaneously into the left shoulder of normal NCr nude mice (18–25 g, 4–6 weeks old) in a mixture of 200 μL of phosphate buffer and Matrigel (v / v, 1 / 1). After an average of 3 weeks, the tumor diameter was approximately 10 mm, which was sufficient for biodistribution and PET / CT imaging studies.

[0115] 2. Ga labeling of the compound of formula (B) (hereinafter referred to as L41) 68 Ga labeling

[0116] 2.1 Dissolve 1.0 μmol of L41 in 1.0 mL of 0.25 M sodium acetate solution.

[0117] 2.2 Elute a germanium-gallium generator with 4 mL of 0.05 M hydrochloric acid solution to prepare 68 GaCl 3 eluate.

[0118] 2.3 Take 1 μmol of L41 solution, add it to the eluate with an activity of 1 mCi, and then add 300 μL of 0.25 M sodium acetate solution. React at 95 °C for 10 min to obtain 68 Ga-L41 complex. The resulting mixture was monitored and quantitatively labeled by radio-high performance liquid chromatography, with a purity >97%. The radiochromatogram is specifically as Figure 5 shown, and the peak information shown is as Table 1.

[0119] Table 1

[0120] Number Time Peak Area Peak Height Peak Width Peak Area % Symmetry Factor Type 1 17.167 8572.2 403.2 0.3543 100.000 0.34 MM

[0121] 3. Positron Emission Tomography-Computed Tomography (PET-CT) of Small Animals

[0122] PET-CT and image analysis were performed using a small animal Novel Medical PET-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.

[0123] Under isoflurane anesthesia, approximately 100 μCi of 68 Ga-L41 complex was injected into the BxPC3 tumor-bearing mice via the tail vein. Static PET-CT images were obtained at 0.5, 1, 3, and 6 hours after intravenous injection for 15 minutes respectively. Compare 68 the imaging effects of the Ga-L41 complex at each time point.

[0124] PET and CT images were acquired using NMSoft workstation software (Beijing Yongxin). The data were given as the percentage of the injected dose per gram of tissue or organ (ID / g) and were determined by decay correction for each sample (normalized to a known weight representing the injected dose). Normalization was performed during statistics, and the standardized uptake value (SUV) was calculated according to the following formula:

[0125] SUV = ([Bq / mL] × [animal body weight (g)] / [injected dose (Bq)])

[0126] 68 The uptake of the Ga-L41 complex in four organs, namely the tumor, heart, muscle, and kidney, at each time point and the uptake ratios between the tumor and the heart, kidney, and muscle, respectively, are as Figure 6 shown in –7. It can be found that after injecting 68 Ga-L41, signals could be detected in the whole body blood pool of mice within a short time, indicating that the albumin-binding fragment in the molecule played a role and increased the in vivo circulation time of the molecule. Moreover, with the increase of time, most of the molecules were excreted through the kidney with urine, and the background signals at normal tissues throughout the body gradually decreased, while the signals at the tumor tissue gradually increased, suggesting that the molecule showed specific enrichment at the tumor tissue over time. After 6 hours of injection, the tumor / heart ratio could reach about 2.28 and had a tendency to continue to increase. The above results all indicated that L41 had good stability, targeting, and specificity.

[0127] 4. Biodistribution Study

[0128] The example 68 Ga-L41 (100 μCi) compound was intravenously injected into BxPC3 tumor-bearing NCr nude mice. After euthanasia at 0.5, 1, and 3 h after administration, anatomical specimens were taken, with 5 mice at each time point. The blocking group was co-injected with L41 solution (25 mg / kg) and 68 Ga-L41. After euthanasia 1 hour later, anatomical specimens were taken, with 5 mice in the blocking group.

[0129] Tissues and organs of interest were collected and weighted and radioactivity counted using a gamma counter.

[0130] The biodistribution data were given as the percentage of the injected dose per gram of tissue or organ (%ID / g) and were determined by decay correction for each sample (normalized to a known weight representing the injected dose).

[0131] 68 The uptake values of the Ga-L41 complex in various major organ tissues at each time point and the uptake situation after blocking are shown by Figure 8 It can be found that, similar to the results of the PET imaging experiment, after injecting 68After Ga-L41 injection, the uptake in normal tissues throughout the body gradually decreased, while the uptake in tumor tissues gradually increased, reaching 20.1% ID / g 3 hours after injection, suggesting that the molecule showed specific enrichment in tumor tissues over time. Meanwhile, the blocking experiment results showed that one hour after co-injection of an excessive amount of the cold precursor drug L41, the uptake of the radioactive probe 68 Ga-L41 in tumor tissues decreased significantly (18.73% ID / g vs 5.98% ID / g), but the uptake of 68 Ga-L41 in the remaining normal tissues did not change significantly. The above results all indicated that L41 had good stability, targeting and specificity.

[0132] 5. Statistical Analysis

[0133] Statistical analysis was performed using the two-sided unpaired t-test in GraphPad 6. A probability (p) value less than 0.05 was considered statistically significant.

[0134] The above embodiments are only the preferred embodiments of the present application and cannot be used to limit the scope of protection of the present application. Any non-substantive changes and substitutions made by those skilled in the art based on the present application fall within the scope of protection required by the present application.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that, Comprising the moiety of formula (A) or consisting thereof, wherein, R1 and R2 each comprise a peptide sequence in which arginine, glycine or sarcosine, and aspartic acid are sequentially linked; Z is a moiety of formula (A1), a moiety of formula (A2), or a long-chain fatty acid, wherein Q1, Q2, Q3, Q4, and Q5 are each independently selected from the group consisting of -H, -F, -Cl, -Br, -I, -SF3, -SF2Cl, -SF5, -SF4Cl, C1–C6 straight-chain or branched-chain alkyl, C1–C6 straight-chain or branched-chain fluoroalkyl, and C1–C6 straight-chain or branched-chain fluoroalkoxy; m is an integer selected from between 4 and 30; n is an integer selected from between 4 and 30; x is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; y is an integer selected from the group consisting of 1, 2, 3, 4, 5, and 6; and z is 0 or 1.

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein, R1 is a cyclic peptide and further comprises lysine; Optionally, R1 is a cyclic peptide comprising a tripeptide sequence in which L-arginine, glycine or sarcosine, and L-aspartic acid are sequentially linked, and L-lysine; Optionally, R1 is a cyclic peptide composed of 4 to 7 amino acids; Optionally, R1 is a cyclic peptide composed of 5 amino acids; Optionally, R1 is the cyclic peptide shown in SEQ ID NO:1 or SEQ ID NO:2; Optionally, R1 is the cyclic peptide shown in SEQ ID NO:1; and / or R2 is a cyclic peptide and further comprises lysine; Optionally, R2 is a cyclic peptide comprising a tripeptide sequence in which L-asparagine, glycine or sarcosine, and L-arginine are sequentially linked, and L-lysine; Optionally, R2 is a cyclic peptide composed of 4 to 7 amino acids; Optionally, R2 is a cyclic peptide composed of 5 amino acids; Optionally, R2 is the cyclic peptide shown in SEQ ID NO:1 or SEQ ID NO:2; Optionally, R2 is the cyclic peptide shown in SEQ ID NO:

1.

3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, characterized in that, Z is a moiety of formula (A1), wherein Q1 is -H; and / or Q2 is -H; and / or Q3 is selected from the group consisting of -H, -F, -Cl, -Br, -I, -CH2F, -CHF2, and -CF3; and / or Q4 is -H or -F; and / or Q5 is -H or -F; Optionally, Q1 is -H; Q2 is -H; Q3 is -Br; Q4 is -H; and Q5 is -H.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein, m is 4; and / or n is 4; and / or x is 3; and / or y is 3; and / or z is 1; and / or The part in formula (A) is 5. The compound according to any one of claims 1 to 4, characterized in that, The compound is a compound of formula (B), 6. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 in radiolabeling or preparing a radiolabeling reagent.

7. A radioactive nuclide preparation, characterized in that, Comprising: The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5; and A radionuclide chelated with the compound or a pharmaceutically acceptable salt thereof.

8. The radionuclide preparation according to claim 7, characterized in that, The radioactive nuclides include at least one selected from the group consisting of 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 includes at least one selected from the group consisting of 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 includes 68 Ga.

9. A process for preparing the compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or the radionuclide preparation according to claim 7 or 8, characterized in that, Comprising: Contacting a compound of formula (1) or a protected derivative thereof with a compound of formula (2) or a protected derivative thereof to obtain a compound of formula (3); Contacting a compound of formula (3) or a protected derivative thereof with a compound of formula (4) or a protected derivative thereof to obtain a compound of formula (5); and Contacting a compound of formula (5) or a protected derivative thereof with a compound of formula (6) or a protected derivative thereof to obtain a compound of formula (A), 10. Use of the compound according to any one of claims 1 to 5, or the radionuclide preparation according to any one of claims 7 to 8, in the preparation of a medicament for detecting cancer, diagnosing cancer, monitoring cancer progression, monitoring cancer treatment or treating cancer; Optionally, the cancer is pancreatic cancer.

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