WO2024114792A1 - 异二聚体及其放射性医药用途 - Google Patents
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
Definitions
- the present application relates to the field of molecular imaging, and more specifically to a heterodimer and its radioactive medical use.
- Dual-target molecular probes fill this gap. Since many tumor cells overexpress multiple tumor-specific receptors on their surfaces, probes that can recognize multiple targets have higher targeting affinity and efficiency than single-receptor probes. Dual-target molecular probes may target two receptors/proteins on the surface of cancer cells, tumor microenvironment, or immune cells, and their specific interactions with two different targets enable these dual-target probes to show enhanced affinity. Due to the increased affinity and improved pharmacokinetic characteristics, the specific uptake of dual-target molecular probes in tissues is superior to that of corresponding monomeric imaging agents. Therefore, the strategy for developing new, highly specific molecular probes for tumor diagnosis and treatment is to convert low-affinity single-target ligands into high-affinity dual/multi-target ligands through a multivalent interaction strategy to increase the maximum binding capacity.
- Angiogenesis is the process of new blood vessels being formed from existing blood vessels. It is widely considered to be an important way to ensure that fast-growing tumor tissues take in nutrients and oxygen. It is also closely related to the invasion and metastasis of tumor cells. Since tumor growth and metastasis are highly dependent on angiogenesis, this phenomenon is considered to be a major target for tumor diagnosis and treatment.
- the tumor angiogenesis process is stimulated by a variety of growth factors, including integrin ⁇ v ⁇ 3 receptors and CD13 receptors.
- Integrin ⁇ v ⁇ 3 plays an important role in tumor angiogenesis and is a receptor for extracellular matrix proteins with the RGD tripeptide sequence. These include vitreous protein, fibronectin, fibrinogen, collagen, von Willebrand factor, osteopontin, and adenovirus particles. Integrin ⁇ v ⁇ 3 is expressed at low levels in epithelial cells and mature endothelial cells, but is overexpressed in activated endothelial cells and some tumor cells in tumor angiogenesis. Studies have shown that integrin ⁇ v ⁇ 3 is highly correlated with tumor growth, invasion, and metastasis, and is a key molecular target for early detection and treatment of rapidly growing solid tumors.
- 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 pancreatic cancer, breast cancer, ovarian cancer, melanoma, etc. CD13 is also involved in tumor angiogenesis. CD13 is present in tumor endothelial cells, but not in normal tissue blood vessels.
- Targeted radiation therapy is an important tumor treatment method, especially for metastatic and highly diffuse cancers that are ineffective with surgery or traditional radiotherapy.
- This therapy uses carriers or interventional techniques to specifically concentrate radionuclides in diseased tissues or cells.
- the radiation particles produced by the radionuclides move in biological tissues, accompanied by energy transfer and ionization.
- the energy generated by this process can directly break the chemical bonds of biological macromolecules such as nucleic acids and proteins, leading to changes in molecular structure and function.
- DNA breakage and synthesis disorders can cause cell cycle arrest or apoptosis in damaged cells, thereby exerting a therapeutic effect.
- Targeted radiation therapy usually uses a targeting agent/carrier (e.g., antibodies, peptides, or small molecules) and is labeled with therapeutic radioactive isotopes (e.g., 177 Lu, 90 Y, 131 I, 89 Sr, 32 P, etc. that emit beta rays, and 223 Ra, 212 Bi, 225 Ac, etc. that emit alpha rays) to deliver cytotoxic doses of radioactive rays to target cancer cells.
- therapeutic radioactive isotopes e.g., 177 Lu, 90 Y, 131 I, 89 Sr, 32 P, etc. that emit beta rays, and 223 Ra, 212 Bi, 225 Ac, etc. that emit alpha rays
- the currently commonly used treatments are:
- the half-life of therapeutic radionuclides is usually long to achieve continuous internal radiation, such as 177 Lu half-life of 6.7 days, 131 I half-life of 8.1 days, and 32 P half-life of 14.3 days.
- the drug of the targeting agent/carrier In order to maximize the therapeutic effect of radionuclides, when designing the drug of the targeting agent/carrier, it is necessary to make its biological half-life match the radioactive half-life of the paired radionuclide as much as possible.
- the current peptide targeting carriers generally have the defects of low tumor uptake rate and high in vivo clearance rate. Radiotherapy using peptides as targeting carriers usually leads to insufficient radiation dose at the tumor tissue, which limits its application in the field of tumor treatment.
- Albumin has been widely explored as a drug carrier due to its high biocompatibility, strong non-antigenicity, good biodegradability, and easy surface modification. To date, several albumin-based nano-drug delivery systems have been successfully transformed into clinical drugs, significantly improving the pharmacokinetics and tumor accumulation of drugs, thereby increasing the therapeutic efficiency of drugs and reducing side effects.
- albumin binding fragments can be introduced into carrier molecules, so that in vivo, the targeting molecules labeled with radioisotopes can bind to albumin, their blood circulation time and half-life can be significantly extended, and their pharmacokinetic properties can also be improved.
- the large particle size of albumin and the EPR effect of tumor tissue can be used to increase the targeting of targeting probes and radioisotopes, 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 targeting probes and radioisotopes can be increased.
- albumin loading technology will also lead to increased uptake of radioactive targeting peptides by healthy organs, resulting in corresponding side effects.
- a compound comprising or consisting of the structure of formula (A).
- Z 1 is –L 1 R 1 or –H, and Z 2 is –L 2 R 2 or –H, provided that Z 1 is –L 1 R 1 and/or Z 2 is –L 2 R 2 ;
- L 1 is –(PEG) m –, and m is an integer selected from 4 to 30;
- L 2 is –(PEG) n –, and n is an integer selected from 4 to 30;
- R 1 comprises a peptide sequence sequentially linked by arginine, glycine or sarcosine, and aspartic acid;
- R 2 comprises a peptide sequence sequentially linked by asparagine, glycine or sarcosine, cysteine, and arginine;
- R 3 is a group of formula (I) or a group of formula (II)
- R 4 is a group of formula (III), a group of formula (IV) or a long-chain fatty acid, and Q 1 , Q 2 , Q
- the present application provides a radionuclide preparation, comprising or consisting of a compound of the present application and a radionuclide chelated therewith.
- the present application provides a method for preparing the compound or radionuclide preparation of the present application, comprising: obtaining a first compound comprising a structure of formula (A1); obtaining a second compound comprising a structure of formula (A2); forming an amide bond between the -N* H2 group of the second compound and the -C*OOH group of the compound of formula (I′) or the compound of formula (II′) or a compound protected by its -N* H2 group to obtain a third compound comprising a group of formula (I′′) or a group of formula (II′′), and reacting the third compound with the first compound to obtain a fourth compound; and forming an amide bond between the -N* H2 group of the group of formula (I′′) or the group of formula (II′′) of the fourth compound and the -C*OOH group of the compound of formula (III′).
- the present application provides the use of the compound or radionuclide preparation of the present application in the preparation of a drug for detecting cancer, diagnosing cancer, monitoring cancer progression, monitoring cancer treatment, or treating cancer.
- the use of the compounds of the present application in radionuclide labeling is provided. In some embodiments, the use of the compounds of the present application in the preparation of radionuclide labeled targeting molecules is provided. In some embodiments, the use of the compounds of the present application in the preparation of radionuclide labeling agents is provided. In some embodiments, the use of the compounds of the present application in the preparation of drug carriers is provided. In some embodiments, the use of the compounds of the present application as drug carriers is provided. In some embodiments, the use of the compounds of the present application or radionuclide preparations in the preparation of drugs for detecting cancer, diagnosing cancer, monitoring cancer progression, monitoring cancer treatment or treating cancer is provided. In some embodiments, the use of the compounds of the present application or radionuclide preparations in detecting cancer, diagnosing cancer, monitoring cancer progression, monitoring cancer treatment or treating cancer is provided.
- compounds of the present application for radionuclide labeling are provided.
- targeting molecules labeled with radionuclides are provided, including compounds of the present application, or consisting thereof.
- radionuclide labeling agents are provided, including compounds of the present application, or consisting thereof.
- drug carriers are provided, including compounds of the present application, or consisting thereof.
- preparations for detecting cancer, diagnosing cancer, monitoring cancer progression, monitoring cancer treatment, or treating cancer are provided, including In some embodiments, a compound or radionuclide preparation of the present application is provided for detecting cancer, diagnosing cancer, monitoring cancer progression, monitoring cancer treatment or treating cancer.
- a method of radionuclide labeling comprising administering the complex chelating a radionuclide, or the radionuclide preparation. In some embodiments, a method of radionuclide labeling is provided, comprising contacting the complex chelating a radionuclide, or the radionuclide preparation, with an object to be labeled with the radionuclide.
- a method for detecting cancer, diagnosing cancer, monitoring cancer progression, or monitoring cancer treatment comprising: administering the complex of chelated radionuclides, or the radionuclide preparation, to a subject for detecting cancer, diagnosing cancer, monitoring cancer progression, or monitoring cancer treatment; detecting radionuclides and determining the level and location of radionuclides in the subject being tested; and comparing the level and location with the level and location of the radionuclide in an otherwise identical location from an unaffected subject or an unaffected area of the subject being tested, wherein a higher level or different location of the radionuclide in the subject being tested compared to the level and location of the radionuclide in the sample from an unaffected subject or from an unaffected area of the subject being tested indicates that the subject being tested has cancer, thereby detecting cancer, diagnosing cancer, monitoring cancer progression, or monitoring cancer treatment.
- a method for treating cancer in a patient comprising administering the complex of chelated radionuclides, or the radionuclide preparation. In some embodiments, a method for treating cancer in a patient is provided, comprising contacting the complex of chelated radionuclides, or the radionuclide preparation, with a patient.
- FIG. 1 is an electrospray mass spectrometry (ESI-MS) diagram of the precursor NGR-PEG 4 -BCN in some embodiments of the present application.
- ESI-MS electrospray mass spectrometry
- FIG. 2 is an electrospray mass spectrum of the precursor RGD-PEG 4 -Lys-DOTA-N 3 in some embodiments of the present application.
- FIG. 3 is an electrospray mass spectrum of the precursor RGD-PEG 4 -Lys(-RH)-DOTA-N 3 in some embodiments of the present application.
- FIG. 4 is an electrospray mass spectrum of the precursor RGD-PEG 4 -Lys(-RH)-DOTA-click-PEG 4 -NGR in some embodiments of the present application.
- FIG5 is an electrospray mass spectrum of the compound RGD-PEG 4 -Lys(-RR 1 )-DOTA-click-PEG 4 -NGR in some embodiments of the present application.
- Figure 6 shows the uptake of 68 Ga-L00, 68 Ga-L11, 68 Ga-L12, 68 Ga-L13, and 68 Ga-L21 conjugates in tumors, muscles, and kidneys at various time points after intravenous injection in some embodiments of the present application.
- A is the uptake of tumors
- B is the uptake of muscles
- C is the uptake of kidneys
- D is the uptake comparison of 68 Ga-L11, 68 Ga-L12, 68 Ga-L13, and 68 Ga-L21 conjugates in tumors, muscles, and kidneys at 5 hours.
- the vertical axis is the standard uptake value (SUV).
- Figure 7 shows the uptake of 68 Ga-L00, 68 Ga-L11, 68 Ga-L12, 68 Ga-L13, and 68 Ga-L21 conjugates in tumors, muscles, and kidneys at various time points after intravenous injection in some embodiments of the present application.
- A is the in vivo distribution of a representative animal selected from each conjugate group 5 hours after drug injection;
- B is the tumor/muscle ratio of each conjugate group at each time point (tumor uptake divided by muscle uptake, expressed as a percentage);
- C is the tumor/kidney ratio of each conjugate group at each time point (tumor uptake divided by kidney uptake, expressed as a percentage).
- FIG8 shows static SPECT-CT images of mice at 4, 24, 48, 72 and 96 hours after intravenous injection of 177 Lu-L11 compound.
- FIG9 shows the distribution of radioactivity in various tissues of mice 24 hours after intravenous injection of four complexes: 177 Lu-L11, 177 Lu-L12, 177 Lu-D-L11, and 177 Lu-L11-1.
- Figure 10 is formula (A).
- the term “about” refers to approximation, in the range of about or near.
- the term “about” modifies the range by expanding the limit above or below the provided numerical value.
- the term “about” is used herein to change the numerical value up and down by 10% from the provided value.
- the term “about” refers to adding or subtracting 20% of the numerical value of the number modified by it.
- “about 50%” refers to within the range of 45%-55%.
- the numerical ranges mentioned herein by endpoints include all integers and fractions contained in the 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”.
- compositions e.g., a device, composition, or method, etc.
- elements e.g., each unit of a device, each component of a composition, or substantial steps of a method, etc.
- Consisting of means excluding the combination of other elements (unit components and substantial method steps. Embodiments defined by each of these transition terms are within the scope of the present invention.
- amino acid can be used interchangeably with “amino acid residue”, and can 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 free amino acids or residues of peptides.
- amino acid is intended to include natural and synthetic amino acids, and includes D- and L-type amino acids.
- Standard amino acids refer to any of the twenty standard L-amino acids (including glycine) commonly found in naturally occurring peptides.
- D-type and “L-type” amino acids as described herein, unless otherwise specified, are not intended to exclude amino acids that do not have chirality, such as glycine.
- Non-standard amino acid residues refer to any amino acid other than standard amino acids, whether or not they are prepared synthetically or derived from natural sources.
- synthetic amino acids also include chemically modified amino acids, including but not limited to salts, amino acid derivatives (e.g., amides) and substitutes.
- 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 change the circulation half-life of the peptide without adversely affecting its activity, and in particular amino acids located at the C-terminus or N-terminus.
- disulfide bonds may be present or absent in the peptides of the present invention.
- the term "pharmaceutical composition” refers to a composition comprising at least one active ingredient, wherein the composition is acceptable for studying a specific, effective result in a mammal (such as, but not limited to, a human). Based on the needs of the skilled person, one of ordinary skill in the art will understand and appreciate the techniques suitable for determining whether an active ingredient has a desired effective effect.
- the term "pharmaceutically acceptable carrier” refers to a chemical composition with which a suitable compound or derivative can be combined and which, after combination, can be used to administer the suitable compound to a subject.
- physiologically acceptable ester or salt refers to an ester or salt form of the active ingredient that is compatible with any other ingredients of the pharmaceutical composition and that is not deleterious to a subject to whom the composition is administered.
- pharmaceutically acceptable means physiologically tolerable for human or veterinary use.
- composition includes formulations for both human and veterinary use.
- plurality means at least two.
- polynucleotide refers to a single strand or parallel and antiparallel strands of nucleic acid.
- a polynucleotide can be a single-stranded or double-stranded nucleic acid.
- polypeptide refers to a polymer composed of amino acid residues linked by peptide bonds, their related naturally occurring structural variants, and synthetic non-naturally occurring analogs thereof.
- synthetic peptide or polypeptide refers to a peptide or polypeptide that does not occur naturally.
- a synthetic peptide or polypeptide can be synthesized using an automatic peptide synthesizer.
- the term “and/or” refers to and encompasses 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 included alone, or may include any combination of two or more listed items.
- the composition may include A alone; B alone; C alone; D alone; a combination of A and B; a combination of A and C; a combination of A and D; a combination of B and C; a combination of B and D; a combination of C and D; a combination of A, B and C; a combination of A, B and D; a combination of A, C and D; a combination of B, C and D; or a combination of A, B, C, and D.
- the compounds or ions of the present application include a plurality of variable groups.
- One of ordinary skill in the art will recognize that the combinations of groups contemplated by the present application are chemically permitted combinations of compounds or ions.
- the stereochemistry of chiral centers can be defined according to the conventions of those skilled in the art, using solid line wedged bonds.
- Indicate groups facing away from the page (toward the reader) and use a hashed bond Indicates groups facing inward (away from the reader) of the paper. If such a representation is used, it can be understood as indicating that the chemical Any bond not specifically represented by a solid wedge bond or a dashed wedge bond herein should be considered as not specifically indicating whether the bond is facing out of the paper, facing into the paper, or located in the paper, but does not prevent it from facing out of the paper or facing into the paper when chemically allowed.
- the term “isomer” means a compound having the same molecular formula but different bonding properties or order of its atoms or the arrangement of its atoms in space.
- the term “stereoisomer” means an isomer with different arrangement of atoms in space;
- 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 does not belong to an enantiomer and has an opposite configuration at one or more asymmetric centers.
- a compound 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 asymmetric centers and designated as R-configuration or S-configuration, or designated as right-handed or left-handed in the way in which the molecule rotates the plane of polarized light.
- Chiral compounds can exist as individual enantiomers or as a mixture thereof, for example, as a racemic mixture.
- the compounds of the present application may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. It is considered that 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, form part of the present application.
- H hydrogen atoms
- C carbon atoms
- (PEG) n herein means polyethylene glycol composed of n ethylene glycol monomers.
- (PEG) m herein.
- (PEG) 4 herein means polyethylene glycol composed of 4 ethylene glycol monomers.
- Z 1 is –L 1 R 1 . In some embodiments, Z 1 is H. In some embodiments, Z 2 is –L 2 R 2 . In some embodiments, Z 2 is –H. In some embodiments, Z 1 is –L 1 R 1 and/or Z 2 is –L 2 R 2 . In some embodiments, Z 1 is –L 1 R 1 and Z 2 is –L 2 R 2 . In some embodiments, Z 1 is –L 1 R 1 and Z 2 is –H. In some embodiments, Z 1 is –H and Z 2 is –L 2 R 2 .
- 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.
- 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.
- 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.
- 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.
- n is 31. In some embodiments, n is 32. In some embodiments, n is 33. In some embodiments, n is 34. In some embodiments, n is 35. In some embodiments, n is 36. 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.
- R 1 includes a tripeptide sequence sequentially linked by arginine, glycine or sarcosine, and aspartic acid. In some embodiments, R 1 includes a tripeptide sequence sequentially linked by L-arginine, glycine or sarcosine, and L-aspartic acid. In some embodiments, R 1 includes a tripeptide sequence sequentially linked by L-arginine, glycine, and L-aspartic acid. In some embodiments, R 1 includes a tripeptide sequence sequentially linked by L-arginine, glycine, and L-aspartic acid. In some embodiments, R 1 is a cyclic peptide.
- R 1 is a cyclic peptide consisting of 4 to 7 amino acids. In some embodiments, R 1 is a cyclic peptide consisting of 5 amino acids. In some embodiments, R 1 also includes lysine. In some embodiments, R 1 is a cyclic peptide including lysine. In some embodiments, R 1 is a cyclic peptide consisting of 4 to 7 amino acids including lysine. In some embodiments, R 1 is a cyclic peptide consisting of 5 amino acids including lysine. In some embodiments, R 1 is a cyclic peptide as shown in any one of SEQ ID NOs: 1-2. In some embodiments, R 1 is a cyclic peptide as shown in SEQ ID NO: 1. In some embodiments, R 1 is a cyclic peptide as shown in SEQ ID NO: 2.
- R 2 includes a tripeptide sequence connected in sequence by asparagine, glycine or sarcosine, and arginine. In some embodiments, R 2 includes a tripeptide sequence connected in sequence by L-asparagine, glycine or sarcosine, and L-arginine. In some embodiments, R 2 includes a tripeptide sequence connected in sequence by L-asparagine, glycine, and L-arginine. In some embodiments, R 2 includes a tripeptide sequence connected in sequence by L-asparagine, sarcosine, and L-arginine. In some embodiments, R 2 is a cyclic peptide.
- R 2 is a cyclic peptide consisting of 4 to 7 amino acids. In some embodiments, R 2 is a cyclic peptide consisting of 6 amino acids. In some embodiments, R 2 also includes lysine. In some embodiments, R 2 is a cyclic peptide including lysine. In some embodiments, R 2 is a cyclic peptide consisting of 4 to 7 amino acids including lysine. In some embodiments, R 2 is a cyclic peptide consisting of 6 amino acids including lysine. In some embodiments, R 2 is a cyclic peptide as shown in any one of SEQ ID NOs: 3–6.
- R 2 is a cyclic peptide as shown in SEQ ID NO: 3. In some embodiments, R 2 is a cyclic peptide as shown in SEQ ID NO: 4. In some embodiments, R 2 is a cyclic peptide as shown in SEQ ID NO: 5. In some embodiments, R 2 is a cyclic peptide as shown in SEQ ID NO: 6.
- R 3 is a group of formula (I). In some embodiments, R 3 is a group of formula (II).
- the group of formula (I) is a group of formula (LI) or a group of formula (DI). In some embodiments, the group of formula (II) is a group of formula (L-II) or a group of formula (D-II). In some embodiments, the group R is a group of formula (LI). In some embodiments, the group R is a group of formula (DI). In some embodiments, the group R is a group of formula (L-II). In some embodiments, the group R is a group of formula (D-II). In some embodiments, the group R is selected from the group consisting of a group of formula (LI), a group of formula (DI), a group of formula (L-II), and a group of formula (D-II).
- the compound of formula (I') is a compound of formula (LI') or a compound of formula (DI'). In some embodiments, the compound of formula (II') is a compound of formula (L-II') or a compound of formula (D-II). In some embodiments, the compound of formula (I') is a compound of formula (LI'). In some embodiments, the compound of formula (I') is a compound of formula (DI'). In some embodiments, the compound of formula (II') is a compound of formula (L-II'). In some embodiments, the compound of formula (II') is a compound of formula (D-II).
- the group of formula (I") is a group of formula (LI") or a group of formula (DI") .
- the group of formula (II") is a group of formula (L-II") or a group of formula (D-II) .
- the group of formula (I") is a group of formula (LI") .
- the group of formula (I") is a group of formula (DI") .
- the group of formula (II") is a group of formula (L-II") .
- the group of formula (II") is a group of formula (D-II) .
- R 4 is a group of formula (III). In some embodiments, R 4 is a group of formula (IV). In some embodiments, R 4 is a long-chain fatty acid.
- Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are each independently selected from the group consisting of -H, -F, -Cl, -Br, -I, -CH 2 F, -CHF 2 , and -CF 3.
- Q 3 is selected from the group consisting of -H, -F, -Cl, -Br, -I, -CH 2 F, -CHF 2 , and -CF 3.
- one of Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 is -F.
- two of Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are -F.
- Q 1 is -H. In some embodiments, Q 2 is -H. In some embodiments, Q 3 is -F. In some embodiments, Q 3 is -Cl. In some embodiments, Q 3 is -Br. In some embodiments, Q 3 is -I. In some embodiments, Q 3 is -CH 2 F. In some embodiments, Q 3 is -CHF 2. In some embodiments, Q 3 is -CF 3. In some embodiments, Q 4 is -F. In some embodiments, Q 5 is -F. In some embodiments, Q 4 is -H and Q 5 is -H. In some embodiments, Q 4 is -H and Q 5 is -F. In some embodiments, Q 4 is -F and Q 5 is -H. In some embodiments, Q 4 is -F and Q 5 is -F. In some embodiments, Q 4 is -F and Q 5 is -H. In some embodiments, Q 4 is -F and Q 5 is -F. In some embodiments, Q 4 is
- 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.
- 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.
- 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.
- y is 3, Q1 is -H, Q2 is -H, Q3 is -CF3 , Q4 is -H or -F, and Q5 is -H or -F.
- 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.
- R4 is a group of formula (IIIa), Q4 is -H or -F, and Q5 is -H or -F,
- R 3 is a group of formula (I), x is 3, R 4 is a group of formula (IIIa), Q 4 is H, and Q 5 is H.
- R 3 is a group of formula (I), x is 3, R 4 is a group of formula (IIIa), Q 4 is F, and Q 5 is H.
- R 3 is a group of formula (I), x is 3, R 4 is a group of formula (IIIa), Q 4 is H, and Q 5 is F.
- R 3 is a group of formula (I), x is 3, R 4 is a group of formula (IIIa), Q 4 is H, and Q 5 is F.
- R 3 is a group of formula (II), x is 3, R 4 is a group of formula (IIIa), Q 4 is H, and Q 5 is H.
- R 3 is a group of formula (II), x is 3, R 4 is a group of formula (IIIa), Q 4 is F, and Q 5 is H.
- R 3 is a group of formula (II), x is 3, R 4 is a group of formula (IIIa), Q 4 is H, and Q 5 is F.
- R 3 is a group of formula (II), x is 3, R 4 is a group of formula (IIIa), Q 4 is F, and Q 5 is F.
- Z 1 is -L 1 R 1 and Z 2 is -L 2 R 2 ; and/or m is 4; and/or n is 4.
- x is 3; and/or R 4 is a group of formula (III), and y is 2 or 3.
- R 4 is a group of formula (III); and Q 1 is -H; Q 2 is -H; Q 3 is selected from the group consisting of -H, -F, -Cl, -Br, -I, -CH 2 F, -CHF 2 , and -CF 3 ; Q 4 is -H or -F; and/or Q 5 is -H or -F.
- the compounds of the present application chelate radionuclides.
- the radionuclides 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 or consist of the same.
- the radionuclide comprises 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 or consists thereof. In some embodiments, the radionuclide comprises at least one selected from the group consisting of 68 Ga and 177 Lu or consists thereof. In some embodiments, the radionuclide comprises 68 Ga. In some embodiments, the radionuclide comprises 177 Lu.
- the third compound reacts with the first compound to obtain the fourth compound by a click reaction.
- obtaining the first compound comprises: reacting the R 2 cyclic peptide with bicyclo[6.1.0]nonyne (BCN)-L 2 -N-hydroxysuccinimide (NHS) to obtain the first compound.
- obtaining the second compound comprises: reacting a linear peptide with or without a protecting group of the R 1 cyclic peptide, L 1 -CH 2 CH 2 OH with or without a protecting group, lysine with or without a protecting group, and DO3AtBu-N 3 to obtain the second compound.
- the treatment is radiotherapy.
- the present application develops novel albumin binders that can significantly increase tumor uptake without negatively affecting non-tumor organs, thereby improving the therapeutic index.
- SEQ ID NO:1–6 sequences are shown in Table 2.
- Example L11 compound is not limited thereto. It should be understood by those skilled in the art that the following synthesis examples can be used to prepare the compound L11.
- embodiment L11 may be referred to as "L11" for short, and the same applies to the other embodiments.
- DIEA N,N-diisopropylethylamine
- HPLC High performance liquid chromatography
- the resin was cleaved with a 30% trifluoroethanol solution in dichloromethane for 2 hours. After filtration, the solvent was dried with a rotary evaporator to obtain a product with a protective group.
- Electrospray mass spectrometry results: m/z [M+H] + 1434.96 (chemical formula: C 62 H 103 N 19 O 20 , calculated molecular weight 1433.76).
- the electrospray mass spectrum is shown in FIG2 , where the horizontal axis is mass-to-charge ratio (m/z) and the vertical axis is relative intensity (%).
- Electrospray mass spectrometry results: m/z [M+2H] + 832.25 (chemical formula: C 72 H 119 N 21 O 24 , calculated molecular weight 1661.87).
- the electrospray mass spectrum is shown in FIG3 , where the horizontal axis is mass-to-charge ratio (m/z) and the vertical axis is relative intensity (%).
- the electrospray mass spectrum is shown in FIG4 , where the horizontal axis is mass-to-charge ratio (m/z) and the vertical axis is relative intensity (%).
- Electrospray mass spectrometry results: m/z [M+2H] + 1510.58 (chemical formula: C 136 H 210 F 3 N 33 O 41 , calculated molecular weight 3018.53).
- the electrospray mass spectrum is shown in FIG5 , where the horizontal axis is mass-to-charge ratio (m/z) and the vertical axis is relative intensity (%).
- Example L11 compound 1.0 ⁇ g/mL
- mouse plasma or PBS a constant temperature (37°C) incubation method
- Example L11 compound was dissolved in 1 mL of mouse serum and incubated in vitro at a constant temperature for 0 h, 0.5 h, 1 h, 4 h, 24 h and 48 h, and then the remaining percentage of the drug was determined.
- PBS was used as a negative control group.
- the peak area of the drug and the internal standard was determined by LC-MS/MS, and the ratio was used instead of the drug concentration for calculation.
- BxPC3 human pancreatic cancer cells were taken and implanted into 2 ⁇ 10 6 cells in a mixture of 200 ⁇ L phosphate buffer and matrix gel (v/v, 1/1). The cells were implanted subcutaneously in the left shoulder of normal NCr nude mice (18–25 g, 4–6 weeks old). After an average of 1.5 weeks, the tumors were approximately 10 mm in diameter, which was large enough for biodistribution and SPECT/CT imaging studies.
- Example L11 compound Dissolve 1.0 ⁇ mol of Example L11 compound in 1.0 mL of 0.25 M sodium acetate solution.
- Example L11 compound solution Take 1 ⁇ mol of Example L11 compound solution, add it to the eluent with 1 mCi activity, then add 300 ⁇ L of 0.25M sodium acetate solution, react at 60°C for 10 min, and obtain 68 Ga-L11 complex. The obtained mixture is monitored and quantitatively labeled by radio-HPLC, and the purity is >97%.
- PET-CT Positron emission tomography-computed tomography
- PET-CT and image analysis were performed using a small animal NovelMedcal PET-CT scanner (Beijing Yongxin).
- the maximum tangential and radial half-widths were 1.5 mm at the center of the field of view and 1.8 mm at the edge of the field of view.
- PET and CT images were collected using NMSoft workstation software (Beijing Yongxin), and the data were given as the percentage of injected dose per gram of tissue or organ (ID/g) and determined by decay correction of each sample (standardized to a known weight representing the injected dose). Normalization was performed during statistics, and standardized uptake values (SUVs) were calculated according to the following formula:
- SUV ([Bq/mL] ⁇ [animal weight (g)] / [injection dose (Bq)])
- FIGS. 6 and 7 The uptake of the five complexes in tumor, muscle, and kidney at various time points are shown in FIGS. 6 and 7 .
- the 68 Ga-L11 complex formed by the compound of Example L11 can reach a tumor/kidney ratio of about 1.4 6 hours after injection, and has a tendency to continue to increase, indicating that the compound of Example L11 has good stability, targeting and specificity.
- the 68 Ga-L13 complex also showed a similar trend, but the overall uptake rate in tumor tissue was less than that of the 68 Ga-L11 complex.
- FIG7A shows a representative animal selected from each complex group, showing the in vivo distribution of the drug 5 hours after injection.
- the resulting mixture was monitored and quantitatively labeled (>97%) by radio-HPLC to obtain 177 Lu-L11 complex.
- 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.
- 177 Lu-L11 complex Under isoflurane anesthesia, approximately 500 ⁇ Ci of 177 Lu-L11 complex was injected into BxPC3 tumor-bearing mice via the tail vein, with a total of 4 animals injected. Static SPECT-CT images were obtained for 30 minutes 4, 24, 48, 72, and 96 hours after intravenous injection. The long-term spot effect of 177 Lu-L11 complex was evaluated.
- the 177 Lu-L11, 177 Lu-L12, 177 Lu-D-L11, and 177 Lu-L11-1 complexes (3.7 MBq) of the examples were intravenously injected into BxPC3 tumor-bearing NCr nude mice, and five mice were euthanized at 1, 4, 24, 48, 72, and 120 hours after administration, and samples were obtained after autopsy.
- Tissues and organs of interest were collected and weighted and radioactivity counted using a gamma counter.
- Figure 9 shows the distribution of radioactivity in various tissues of mice 24 hours after intravenous injection of four complexes of 177 Lu-L11, 177 Lu-L12, 177 Lu-D-L11, and 177 Lu-L11-1.
- the vertical axis values are given as the percentage of injected dose per gram of tissue or organ (ID/g) and are determined by decay correction of each sample (standardized to a known weight representing the injected dose).
- the four complexes of 177 Lu-L11, 177 Lu-L12, 177 Lu-D-L11, and 177 Lu-L11-1 are all enriched in the tumor, among which the enrichment degree of 177 Lu-L12 is higher than that of the other three.
- these complexes are also enriched in the kidney to a certain extent, and there is a smaller amount of enrichment in the spleen and uterus.
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Abstract
提供了一种包括如摘要附图所示的结构的化合物，还提供了其在放射性核素标记或制备放射性核素标记试剂中的用途。还提供了一种放射性核素制剂，包括了包括如摘要附图所示的结构的化合物。
Description
本申请涉及分子成像领域，更具体涉及一种异二聚体及其放射性医药用途。
双靶点策略
目前，个体化和精准化医疗已逐渐成为癌症治疗的前沿领域，因此对新型肿瘤靶向成像–治疗一体化的需求也应运而生。目前，肿瘤靶向性成像研究取得了巨大的进展，利用高度特异的肽、抗体和纳米粒子作为靶向分子，通过偶联荧光、核素等信号分子，实现临床肿瘤患者疾病状态的非侵入性诊断，而后能够进行针对性地治疗。然而，虽然一系列单受体靶向肽在体内表现出良好的肿瘤靶向性能，但这些单受体靶向肽存在结合亲和力较低、肿瘤停留时间较短、肿瘤摄取较低等缺点，这在某些情况下，将会导致肿瘤组织处成像对比度和特异性不够理想，探针在肿瘤组织处保留时间短暂等不利于肿瘤诊断治疗的情况。
而双靶点分子探针填补了这一空缺，由于许多肿瘤细胞表面过表达多种肿瘤特异性受体，能够识别多个靶点的探针比单受体探针具有更高的靶向亲和力和效率。双靶点分子探针可能针对癌细胞表面、肿瘤微环境或免疫细胞上的两个受体/蛋白质，其与两个不同靶点的特异性相互作用使这些双靶点探针显示出增强的亲和性。由于亲和力的提高和药代动力学特征的改善，双靶点分子探针在组织中的特异性摄取优于相应的单体显像剂。因此，通过多价相互作用策略，将低亲和力的单靶点配体转化为高亲和力的双/多靶点配体，增加最大结合能力，是发展新型高特异性肿瘤诊疗分子探针的策略。
整合素αvβ3受体及CD13受体与肿瘤新生血管
血管生成是由已有的血管形成新生血管的过程，被广泛认为是保证快速生长的肿瘤组织摄取营养物质和氧气的重要途径，同时也与肿瘤细胞侵袭转移之间存在重要关联。由于肿瘤的生长和转移高度依赖于血管生成，这一现象被认为是肿瘤诊断和治疗的主要靶点。肿瘤血管新生过程是由多种生长因子刺激的，其中就包括了整合素αvβ3受体及CD13受体。
整合素αvβ3在肿瘤血管生成中起着重要作用，是RGD三肽序列的细胞外基质蛋白的受体。其中包括玻璃体蛋白、纤维连接蛋白、纤维蛋白原、胶原、血管性血友病因子、骨桥蛋白和腺病毒颗粒。整合素αvβ3在上皮细胞和成熟内皮细胞中低水平表达，但在肿瘤新生血管的活化内皮细胞和部分肿瘤细胞中过表达。研究表明，整合素αvβ3与肿瘤生长、侵袭和转移过程高度相关，是快速生长的实体肿瘤的早期检测和治疗的关键分子靶点。
CD13是一种膜糖蛋白，功能为细胞外氨肽酶，其特异性配体包含NGR三肽序列。在包括胰腺癌、乳腺癌、卵巢癌、黑色素瘤等肿瘤在内的许多人类实体瘤中都能检测到CD13的高表达。CD13也参与肿瘤血管生成，CD13存在于肿瘤内皮细胞中，但不存在于正常组织血管中。
肿瘤的放射性靶向药物治疗
放射靶向治疗是一种重要的肿瘤治疗方式，特别是用于手术或传统的放射治疗无效的转移性和高度扩散的癌症类别。该疗法利用载体或者介入技术，将放射性核素特异性地浓聚于病变组织或细胞，放射性核素产生的射线粒子在生物组织中运动，伴随着发生能量转移和电离，该过程产生的能量可直接使核酸、蛋白质等生物大分子的化学键断裂，导致分子结构和功能改变，特别是DNA的断裂和合成障碍可造成受损细胞的周期阻滞或细胞凋亡，从而发挥治疗作用。放射靶向治疗通常使用一种靶向剂/载体(例如，抗体、肽或小分子等)和用治疗性放射性同位素(例如，发射β射线的177Lu、90Y、131I、89Sr、32P等，和发射α射线的223Ra、212Bi、225Ac等)标记，向目标癌细胞传递细胞毒性剂量的放射性射线。为了达到治疗效果，目前常用的治
疗型放射性核素的半衰期通常较长，以实现持续性的内辐射，如177Lu半衰期为6.7天、131I半衰期为8.1天、32P半衰期为14.3天。为了使放射性核素的治疗效果最大化，在靶向剂/载体的药物设计时，需要使其生物半衰期尽量与配对使用的放射性核素的放射性半衰期相匹配。然而，目前多肽靶向载体普遍存在肿瘤摄取率低和体内清除率高的缺陷，利用多肽作为靶向载体的放射性疗法通常会导致肿瘤组织处的辐射剂量不足的情况，限制了其在肿瘤治疗领域的应用。
白蛋白载体策略
白蛋白因其生物相容性高、非抗原性强、生物降解性好、易表面修饰等优点而被广泛探索作为药物载体。迄今为止，几种基于白蛋白的纳米给药系统已成功转化为临床药物，显著改善了药物的药代动力学和肿瘤积累，从而提高了药物的治疗效率，降低了副作用。
对于肿瘤放射性治疗领域，通过分子设计，可以向载体分子中引入白蛋白结合片段，从而在体内，标记有放射性同位素的靶向分子能够与白蛋白结合，其血液循环时间和半衰期能够显著延长，并且药代动力学性质也能够得到改善。同时，能够利用白蛋白大粒径和肿瘤组织EPR效应增加靶向探针和放射性同位素的靶向性，并且因为肿瘤组织环境代谢水平高，对白蛋白等营养物质摄取率高，能够增加靶向探针和放射性同位素的肿瘤摄取率。
然而，使用上述白蛋白荷载技术也会导致健康器官对放射性靶向肽的吸收增加，从而产生相应的副作用。
发明内容
在一些实施方式中，提供了一种化合物，包括式(A)结构或由其组成。
其中，Z1为–L1R1或–H，Z2为–L2R2或–H，条件是Z1为–L1R1且/或Z2为–L2R2；L1为–(PEG)m–，且m为选自4至30之间的整数；L2为–(PEG)n–，且n为选自4至30之间的整数；R1包括由精氨酸、甘氨酸或肌氨酸、和天冬氨酸依序连接的肽序列；R2包括由天冬酰胺、甘氨酸或肌氨酸、半胱氨酸、和精氨酸依序连接的肽序列；R3为式(I)基团或式(II)基团，R4为式(III)基团、式(IV)基团或长链脂肪酸，Q1、Q2、Q3、Q4、和Q5各自独立地选自由-H、-F、-Cl、-Br、-I、C1–C6直链或支链烷基、C1–C6直链或支链氟烷基、和C1–C6直链或支链氟烷氧基所组成的组；且x为选自由1、2、3、4、5、6、7、和8所组成的组的整数。
在一些实施方式中，本申请提供了一种放射性核素制剂，包括本申请的化合物和与其螯合的放射性核素，或由其组成。
在一些实施方式中，本申请提供了本申请的化合物或放射性核素制剂的制备方法，包括：获得包括式(A1)结构的第一化合物；获得包括式(A2)结构的第二化合物；第二化合物的-N*H2基团与式(I′)化合物或式(II′)化合物或其-N*H2基团保护的化合物的-C*OOH基团形成酰胺键，得到包括式(I″)基团或式(II″)基团的第三化合物，第三化合物和第一化合物反应得到第四化合物；以及将第四化合物的式(I″)基团或式(II″)基团的-N*H2基团与式(III′)化合物的-C*OOH基团形成酰胺键。
在一些实施方式中，本申请提供了本申请的化合物或放射性核素制剂在制备检测癌症、诊断癌症、监控癌症进展、监控癌症治疗或治疗癌症的药物中的用途。
在一些实施方式中，提供了本申请的化合物在放射性核素标记中的用途。在一些实施方式中，提供了本申请的化合物在制备放射性核素标记的靶向分子的用途。在一些实施方式中，提供了本申请的化合物在制备放射性核素标记试剂中的用途。在一些实施方式中，提供了本申请的化合物在制备药物载体中的用途。在一些实施方式中，提供了本申请的化合物作为药物载体的用途。在一些实施方式中，提供了本申请的化合物或放射性核素制剂在制备检测癌症、诊断癌症、监控癌症进展、监控癌症治疗或治疗癌症的药物中的用途。在一些实施方式中，提供了本申请的化合物或放射性核素制剂在检测癌症、诊断癌症、监控癌症进展、监控癌症治疗或治疗癌症的用途。
在一些实施方式中，提供了用于放射性核素标记的本申请的化合物。在一些实施方式中，提供了放射性核素标记的靶向分子，包括本申请的化合物，或由其组成。在一些实施方式中，提供了放射性核素标记试剂，包括本申请的化合物，或由其组成。在一些实施方式中，提供了药物载体，包括本申请的化合物，或由其组成。在一些实施方式中，提供了检测癌症、诊断癌症、监控癌症进展、监控癌症治疗或治疗癌症的制剂，包
括本申请的化合物或放射性核素制剂，或由其组成。在一些实施方式中，提供了用于检测癌症、诊断癌症、监控癌症进展、监控癌症治疗或治疗癌症的，本申请的化合物或放射性核素制剂。
在一些实施方式中，提供了一种放射性核素标记的方法，包括施用螯合放射性核素的所述复合物，或所述放射性核素制剂。在一些实施方式中，提供了一种放射性核素标记的方法，包括使螯合放射性核素的所述复合物，或所述放射性核素制剂，接触放射性核素所要标记的对象。在一些实施方式中，提供了一种检测癌症、诊断癌症、监控癌症进展、监控癌症治疗的方法，包括：施用螯合放射性核素的所述复合物、或所述放射性核素制剂，到检测癌症、诊断癌症、监控癌症进展或监控癌症治疗的受试者；检测放射性核素和确定放射性核素在所述受试受治疗者体内的水平和位置；以及将所述水平和位置与来自未受影响的受治疗者的其他方面相同的位置或所述受试受治疗者的未受影响的区域的所述放射性核素的水平和位置进行对比，其中与所述放射性核素在来自未受影响的受治疗者或来自所述受试受治疗者的未受影响的区域的所述样品中的水平和位置相比，所述放射性核素在所述受试受治疗者体内的更高水平或不同位置表明所述受试受治疗者患有癌症，从而检测癌症、诊断癌症、监控癌症进展或监控癌症治疗。在一些实施方式中，提供了一种治疗患者的癌症的方法，包括施用螯合放射性核素的所述复合物，或所述放射性核素制剂。在一些实施方式中，提供了一种治疗患者的癌症的方法，包括使螯合放射性核素的所述复合物，或所述放射性核素制剂，接触患者。
图1为本申请的一些实施例中，前体NGR-PEG4-BCN的电喷雾质谱(ESI-MS)图。
图2为本申请的一些实施例中，前体RGD-PEG4-Lys-DOTA-N3的电喷雾质谱图。
图3为本申请的一些实施例中，前体RGD-PEG4-Lys(-R-H)-DOTA-N3的电喷雾质谱图。
图4为本申请的一些实施例中，前体RGD-PEG4-Lys(-R-H)-DOTA-click-PEG4-NGR的电喷雾质谱图。
图5为本申请的一些实施例中，化合物RGD-PEG4-Lys(-R-R1)-DOTA-click-PEG4-NGR的电喷雾质谱图。
图6为本申请的一些实施例中，68Ga-L00、68Ga-L11、68Ga-L12、68Ga-L13、和68Ga-L21缀合物在静脉注射各时间点后的肿瘤、肌肉、和肾脏的摄取。其中A为肿瘤的摄取、B为肌肉的摄取、C为肾脏的摄取，D为68Ga-L11、68Ga-L12、68Ga-L13、和68Ga-L21缀合物肿瘤、肌肉、和肾脏在5小时的摄取比较。纵轴为标准摄取值(standard uptake value，SUV)。
图7为本申请的一些实施例中，68Ga-L00、68Ga-L11、68Ga-L12、68Ga-L13、和68Ga-L21缀合物在静脉注射各时间点后的肿瘤、肌肉、和肾脏的摄取。其中A为各缀合物组各选择一只代表性动物，药物注射5小时后的体内分布情况；B为各时间点各缀合物组的肿瘤/肌肉比值(肿瘤摄取除以肌肉摄取，以百分比表示)；C为各时间点各缀合物组的肿瘤/肾脏比值(肿瘤摄取除以肾脏摄取，以百分比表示)。
图8为177Lu-L11化合物静脉注射4、24、48、72和96小时后的小鼠静态SPECT-CT图像。
图9为177Lu-L11、177Lu-L12、177Lu-D-L11、177Lu-L11-1四种复合物静脉注射24小时后小鼠各组织放射性分布情况。
图10为式(A)。
本文使用单数术语指一个或多于一个。举例来说，“元件”或“一个元件”皆指一个元件或多于一个的元件。
如本文所述，术语“约”指近似，在大约或附近的范围。当结合数值范围使用术语“约”时，其通过扩大界限高于或低于所提供数值来修改该范围。一般来讲，本文使用术语“约”来使数值与所提供值上下变化10％。一方面，术语“约”指加上或减去其所修饰的数的数值的20％。举例来说，“约50％”指在45％–55％的范围内。本文通过端点提及的数值范围包括包含在该范围内的所有整数和分数(例如“1至5”包括1、1.5、2、2.75、3、3.90、4和5)。还应当理解其所有整数和分数视为被术语“约”修饰。
如本文所述，“包含”或“包括”旨在表示组合(例如装置、组合物、或方法等)包括所列举的要素(例如装置的各单元、组合物的各组分、或方法的实质性步骤等)，但不排除其他要素。当用于定义组合物和方法时，“基本上由……组成”意味着排除对于所述目的的组合具有任何重要意义的其他要素。因此，基本上由本文定义的要素组成的组合不排除不会实质上影响要求保护的本发明的基本和新颖特征的其他要素。“由……组成”是指排除其他要素的组合(单元组分和实质性的方法步骤。由这些过渡术语中的每一个定义的实施方案都在本发明的范围内。
术语“氨基酸”可与“氨基酸残基”互换地使用，且可指游离氨基酸和肽的氨基酸残基。从术语使用的上下文将清楚，其是指游离氨基酸还是肽的残基。如本文所述，“氨基酸”意在包括天然的和合成的氨基酸，并包括D-型和L-型氨基酸。“标准氨基酸”指通常发现于天然形成的肽中的二十个标准L-氨基酸(包括甘氨酸)的任何一个。如本文所述的“D-型”和“L-型”氨基酸，除非另有说明，均非意图排除不具有手性的胺基酸，如甘氨酸。“非标准氨基酸残基”指除了标准氨基酸以外的任何氨基酸，无论其是否经合成制备或源自天然来源。如本文所用的，“合成氨基酸”还包括化学修饰的氨基酸，包括但不限于盐、氨基酸衍生物(例如酰胺)和取代物。可通过甲基化、酰胺化、乙酰化或用可改变肽的循环半衰期而不有害地影响其活性的其他化学基团取代来修饰包含在本发明的肽中的氨基酸，且特别是位于C端或N端的氨基酸。另外，本发明的肽中可存在或不存在二硫键。
如本文所述，术语“药物组合物”是指包含至少一种活性成分的组合物，其中对于在哺乳动物(例如但不限于人)中研究特定的、有效的结果，该组合物是可接受的。基于技术人员的需要，本领域普通技术人员将理解和了解适合确定活性成分是否具有期望的有效效果的技术。
如本文所述，术语“药学可接受的载体”指一种化学组合物，其可与合适的化合物或衍生物组合且组合后其可用于对受治疗者施用合适的化合物。
如本文所用的，术语“生理可接受的”酯或盐是指可与药物组合物的任何其他成分相容的活性成分的酯或盐形式，这种形式对待施用该组合物的受治疗者是无害的。
如本文所述，“药学可接受的”是指对于人或兽医应用是生理可耐受的。
如本文所述，“药物组合物”包括用于人和兽医用途的制剂。
如本文所述，“多个”是指至少两个。
如本文所述，“多核苷酸”是指核酸的单链或平行和反向平行链。因此，多核苷酸可以是单链或双链核酸。
如本文所述，“多肽”是指由通过肽键、其相关的天然形成的结构变体和其合成的非天然形成的类似物连接的氨基酸残基、其相关的天然形成的结构变体和合成的非天然形成的类似物组成的聚合物。
如本文所述，“合成肽或多肽”是指非天然形成的肽或多肽。例如，可以使用自动多肽合成仪合成合成肽或多肽。
如本文所述，术语“和/或”是指并且涵盖一个或多个相关联的所列项目的任何和所有可能的组合。当在二个或多个项目的列表中使用时，术语“和/或”表示所列出的项目中的任何一个可以单独被包含，或者可以包含二个或多个所列出的项目的任何组合。例如，如果组、组合、或组合物等，被描述为包括(或包含)组分A、B、C和/或D，则该组合物可以单独包含A；单独包含B；单独包含C；单独包含D；包含A和B的组合；包含A和C的组合；包含A和D的组合；包含B和C的组合；包含B和D的组合；包含C和D的组合；包含A和B和C的组合；包含A和B和D的组合；包含A和C和D的组合；包含B和C和D的组合；或包含A和B和C和D的组合。
如本文所述，本申请的化合物或离子包括多个可变基团。本领域普通技术人员应当认识到，本申请所设想的基团的组合是化学上允许的化合物或离子的组合。
如本文所述，手性中心的立体化学可以根据本领域技术人员的惯例来定义，即使用实线楔形键(wedged bond)指示朝向纸面之外(朝向读者的一侧)的基团、并使用虚线楔形键(hashed bond)指示朝向纸面之内(远离读者的一侧)的基团。如果使用此类表示方式，那么可以理解为指示本文中各化学
结构所示的基团的特定单一立体异构体。本文中任意未具体使用实线楔形键或虚线楔形键表示的键，应视为未具体指示该键是朝向纸面之外、或朝向纸面之内、或位于纸面，但不妨碍其在化学上允许的情况下朝向纸面之外或朝向纸面之内。
如本文所述，术语“异构体”意指，具有相同分子式但其原子的键合性质或顺序或其原子在空间中的排列不同的化合物。其中，术语“立体异构体”意指原子在空间中的排列不同的异构体；术语“对映异构体”意指带有一个或多个不对称中心的立体异构体，彼此互为不可重叠的镜像；术语“非对映异构体”意指在一个或多个不对称中心处具有相反构型的不属于对映异构体的立体异构体。当化合物具有不对称中心时，例如，如果碳原子键合到四个不同的基团，则可以有一对对映异构体。对映异构体可通过其一个或多个不对称中心的绝对构型来表征并指定为R-构型或S-构型，或以其中分子旋转偏振光平面的方式指定为右旋或左旋。手性化合物可以单独的对映异构体或以其混合物存在，例如是以外消旋混合物存在。本申请的化合物可含有不对称或手性中心，并因此以不同的立体异构形式存在。应视为本申请的化合物的所有立体异构体，包括但不限于非对映异构体、对映异构体、和阻转异构体，及其混合物如外消旋混合物，构成本申请的一部分。
如本文所述，特别是在本文的结构式中所示出的原子，都应当视为包括该原子的各个同位素。举例来说，在本文中无论是文字示出的还是结构式中示出或被省略的氢原子(H)，都应当视为包括氢的各个同位素，例如是包括但不限于氕、氘、氚等；在本文中无论是文字示出的还是结构式中示出的碳原子(C)，都应当视为包括碳的各个同位素，例如是包括但不限于12C、13C、14C等。
如本文所述，特别是在本文的结构式中，当符号“*”用于标记原子时，仅是用于标记结构式中的特定原子以便在本申请中指明，并非意指其所标记的原子有本申请未有说明的不同特性。
本文中的表述“(PEG)n”意指由n个乙二醇单体组成的聚乙二醇。本文中的表述“(PEG)m”同理。例如是，本文中的表述“(PEG)4”意指由4个乙二醇单体组成的聚乙二醇。
在一些实施方式中，Z1为–L1R1。在一些实施方式中，Z1为H。在一些实施方式中，Z2为–L2R2。在一些实施方式中，Z2为–H。在一些实施方式中，Z1为–L1R1且/或Z2为–L2R2。在一些实施方式中，Z1为–L1R1且Z2为–L2R2。在一些实施方式中，Z1为–L1R1且Z2为–H。在一些实施方式中，Z1为–H且Z2为–L2R2。
在一些实施方式中，m为选自4至30之间的整数。在一些实施方式中，m为选自4至25之间的整数。在一些实施方式中，m为选自4至20之间的整数。在一些实施方式中，m为选自4至15之间的整数。在一些实施方式中，m为选自4至10之间的整数。在一些实施方式中，m为选自由4、5、6、7、和8所组成的组。在一些实施方式中，m为选自由4、5、和6所组成的组。在一些实施方式中，m为4或5。在一些实施方式中，m为4。在一些实施方式中，m为5。在一些实施方式中，m为6。在一些实施方式中，m为7。在一些实施方式中，m为8。在一些实施方式中，m为9。在一些实施方式中，m为10。在一些实施方式中，m为11。在一些实施方式中，m为12。在一些实施方式中，m为13。在一些实施方式中，m为14。在一些实施方式中，m为15。在一些实施方式中，m为16。在一些实施方式中，m为17。在一些实施方式中，m为18。在一些实施方式中，m为19。在一些实施方式中，m为20。在一些实施方式中，m为21。在一些实施方式中，m为22。在一些实施方式中，m为23。在一些实施方式中，m为24。在一些实施方式中，m为25。在一些实施方式中，m为26。在一些实施方式中，m为27。在一些实施方式中，m为28。在一些实施方式中，m为29。在一些实施方式中，m为30。
在一些实施方式中，n为选自4至30之间的整数。在一些实施方式中，n为选自4至25之间的整数。在一些实施方式中，n为选自4至20之间的整数。在一些实施方式中，n为选自4至15之间的整数。在一些实施方式中，n为选自4至10之间的整数。在一些实施方式中，n为选自由4、5、6、7、和8所组成的组。在一些实施方式中，n为选自由4、5、和6所组成的组。在一些实施方式中，n为4或5。在一些实施方式中，n为4。在一些实施方式中，n为5。在一些实施方式中，n为6。在一些实施方式中，n为7。在一些实施方式中，n为8。在一些实施方式中，n为9。在一些实施方式中，n为10。在一些实施方式中，n为11。在一些实施方式中，n为12。在一些实施方式中，n为13。在一些实施方式中，n为14。在一些实施
方式中，n为15。在一些实施方式中，n为16。在一些实施方式中，n为17。在一些实施方式中，n为18。在一些实施方式中，n为19。在一些实施方式中，n为20。在一些实施方式中，n为21。在一些实施方式中，n为22。在一些实施方式中，n为23。在一些实施方式中，n为24。在一些实施方式中，n为25。在一些实施方式中，n为26。在一些实施方式中，n为27。在一些实施方式中，n为28。在一些实施方式中，n为29。在一些实施方式中，n为30。
在一些实施方式中，R1包括由精氨酸、甘氨酸或肌氨酸、和天冬氨酸依序连接的三肽序列。在一些实施方式中，R1包括由L-精氨酸、甘氨酸或肌氨酸、和L-天冬氨酸依序连接的三肽序列。在一些实施方式中，R1包括由L-精氨酸、甘氨酸、和L-天冬氨酸依序连接的三肽序列。在一些实施方式中，R1包括由L-精氨酸、肌氨酸、和L-天冬氨酸依序连接的三肽序列。在一些实施方式中，R1为环肽。在一些实施方式中，R1为由4至7个氨基酸组成的环肽。在一些实施方式中，R1为由5个氨基酸组成的环肽。在一些实施方式中，R1还包括赖氨酸。在一些实施方式中，R1为包括赖氨酸的环肽。在一些实施方式中，R1为包括赖氨酸的由4至7个氨基酸组成的环肽。在一些实施方式中，R1为包括赖氨酸的由5个氨基酸组成的环肽。在一些实施方式中，R1为SEQ ID NO:1–2任一所示的环肽。在一些实施方式中，R1为SEQ ID NO:1所示环肽。在一些实施方式中，R1为SEQ ID NO:2所示环肽。
在一些实施方式中，R2包括由天冬酰胺、甘氨酸或肌氨酸、和精氨酸依序连接的三肽序列。在一些实施方式中，R2包括由L-天冬酰胺、甘氨酸或肌氨酸、和L-精氨酸依序连接的三肽序列。在一些实施方式中，R2包括由L-天冬酰胺、甘氨酸、和L-精氨酸依序连接的三肽序列。在一些实施方式中，R2包括由L-天冬酰胺、肌氨酸、和L-精氨酸依序连接的三肽序列。在一些实施方式中，R2为环肽。在一些实施方式中，R2为由4至7个氨基酸组成的环肽。在一些实施方式中，R2为由6个氨基酸组成的环肽。在一些实施方式中，R2还包括赖氨酸。在一些实施方式中，R2为包括赖氨酸的环肽。在一些实施方式中，R2为包括赖氨酸的由4至7个氨基酸组成的环肽。在一些实施方式中，R2为包括赖氨酸的由6个氨基酸组成的环肽。在一些实施方式中，R2为SEQ ID NO:3–6任一所示的环肽。在一些实施方式中，R2为SEQ ID NO:3所示环肽。在一些实施方式中，R2为SEQ ID NO:4所示环肽。在一些实施方式中，R2为SEQ ID NO:5所示环肽。在一些实施方式中，R2为SEQ ID NO:6所示环肽。
在一些实施方式中，R3为式(I)基团。在一些实施方式中，R3为式(II)基团。
在一些实施方式中，式(I)基团为式(L-I)基团或式(D-I)基团。在一些实施方式中，式(II)基团为式(L-II)基团或式(D-II)基团。在一些实施方式中，基团R为式(L-I)基团。在一些实施方式中，基团R为式(D-I)基团。在一些实施方式中，基团R为式(L-II)基团。在一些实施方式中，基团R为式(D-II)基团。在一些实施方式中，基团R选自由式(L-I)基团、式(D-I)基团、式(L-II)基团、式(D-II)基团所组成的组。
在一些实施方式中，式(I′)化合物为式(L-I′)化合物或式(D-I′)化合物。在一些实施方式中，式(II′)化合物为式(L-II′)化合物或式(D-II)化合物。在一些实施方式中，式(I′)化合物为式(L-I′)化合物。在一些实施方式中，式(I′)化合物为式(D-I′)化合物。在一些实施方式中，式(II′)化合物为式(L-II′)化合物。在一些实施方式中，式(II′)化合物为式(D-II)化合物。在一些实施方式中，式(I″)基团为式(L-I″)基团或式(D-I″)基团。在一些实施方式中，式(II″)基团为式(L-II″)基团或式(D-II)基团。在一些实施方式中，式(I″)基团为式(L-I″)基团。在一些实施方式中，式(I″)基团为式(D-I″)基团。在一些实施方式中，式(II″)基团为式(L-II″)基团。在一些实施方式中，式(II″)基团为式(D-II)基团。
在一些实施方式中，R4为式(III)基团。在一些实施方式中，R4为式(IV)基团。在一些实施方式中，R4为长链脂肪酸。
在一些实施方式中，Q1、Q2、Q3、Q4、和Q5各自独立地选自由-H、-F、-Cl、-Br、-I、-CH2F、-CHF2、和-CF3所组成的组。在一些实施方式中，Q3选自由-H、-F、-Cl、-Br、-I、-CH2F、-CHF2、和-CF3所组成的组。在一些实施方式中，Q1、Q2、Q3、Q4、和Q5中的一个为-F。在一些实施方式中，Q1、Q2、Q3、Q4、和Q5中的二个为-F。在一些实施方式中，Q1为-H。在一些实施方式中，Q2为-H。在一些实施方式中，Q3为-F。在一些实施方式中，Q3为-Cl。在一些实施方式中，Q3为-Br。在一些实施方式中，Q3为-I。在一些实施方式中，Q3为-CH2F。在一些实施方式中，Q3为-CHF2。在一些实施方式中，Q3为-CF3。在一些实施方式中，Q4为-F。在一些实施方式中，Q5为-F。在一些实施方式中，Q4为-H且Q5为-H。在一些实施方式中，Q4为-H且Q5为-F。在一些实施方式中，Q4为-F且Q5为-H。在一些实施方式中，Q4为-F且Q5为-F。
一些实施方式中，x选自由1、2、3、4、5、6、7、和8所组成的组。在一些实施方式中，x选自由1、2、3、4、5、6、和7所组成的组。在一些实施方式中，x选自由1、2、3、4、5、和6所组成的组。在一些实施方式中，x选自由1、2、3、4、和5所组成的组。在一些实施方式中，x选自由1、2、3、和4所组成的组。在一些实施方式中，x选自由1、2、和3所组成的组。在一些实施方式中，x选自由2、3、和4所组成的组。在一些实施方式中，x选自由3、4、和5所组成的组。在一些实施方式中，x为2或3。在一些实施方式中，x为3或4。在一些实施方式中，x为1。在一些实施方式中，x为2。在一些实施方式中，x为3。在一些实施方式中，x为4。在一些实施方式中，x为5。在一些实施方式中，x为6。在一些实施方式中，x为7。在一些实施方式中，x为8。
在一些实施方式中，y选自由1、2、3、4、5、和6所组成的组。在一些实施方式中，y选自由1、2、3、4、和5所组成的组。在一些实施方式中，y选自由1、2、3、和4所组成的组。在一些实施方式中，y选自由1、2、和3所组成的组。在一些实施方式中，y选自由2、3、和4所组成的组。在一些实施方式中，y选自由3、4、和5所组成的组。在一些实施方式中，y选自由4、5、和6所组成的组。在一些实施方式中，y为2或3。在一些实施方式中，y为3或4。在一些实施方式中，y为1。在一些实施方式中，y为2。在一些实施方式中，y为3。在一些实施方式中，y为4。在一些实施方式中，y为5。在一些实施方式中，y为6。
在一些实施方式中，y为3，Q1为-H，Q2为-H，Q3为-CF3，Q4为-H或-F，且Q5为-H或-F。在一些实施方式中，x为3，y为3，Q1为-H，Q2为-H，Q3为-CF3，Q4为-H或-F，且Q5为-H或-F。在一些实施方式中，R4为式(IIIa)基团，Q4为-H或-F，且Q5为-H或-F，
在一些实施方式中，R3为式(I)基团，x为3，R4为式(IIIa)基团，Q4为H，且Q5为H。在一些实施方式中，R3为式(I)基团，x为3，R4为式(IIIa)基团，Q4为F，且Q5为H。在一些实施方式中，R3为式(I)基团，x为3，R4为式(IIIa)基团，Q4为H，且Q5为F。在一些实施方式中，R3为式(I)基团，x为3，R4为式(IIIa)基团，Q4为F，且Q5为F。在一些实施方式中，R3为式(II)基团，x为3，R4为式(IIIa)基团，Q4为H，且Q5为H。在一些实施方式中，R3为式(II)基团，x为3，R4为式(IIIa)基团，Q4为F，且Q5为H。在一些实施方式中，R3为式(II)基团，x为3，R4为式(IIIa)基团，Q4为H，且Q5为F。在一些实施方式中，R3为式(II)基团，x为3，R4为式(IIIa)基团，Q4为F，且Q5为F。
在一些实施方式中：Z1为–L1R1且Z2为–L2R2；且/或m为4；且/或n为4。在一些实施方式中：x为3；且/或，R4为式(III)基团，且y为2或3。在一些实施方式中：R4为式(III)基团；且，Q1为-H；Q2为-H；Q3为选自由-H、-F、-Cl、-Br、-I、-CH2F、-CHF2、和-CF3所组成的组；Q4为-H或-F；且/或Q5为-H或-F。
在一些实施方式中，本申请的化合物螯合放射性核素。在一些实施方式中，所述放射性核素包括选自由44Sc、47Sc、62Cu、64Cu、67Cu、66Ga、67Ga、68Ga、86Y、90Y、89Zr、99mTc、110mIn、111In、113mIn、114mIn、177Lu、188Re、203Pb、212Pb、212Bi、213Bi、211At、223Ra、和225Ac所组成的组中的至少一个或由其组成。在一些实施方式中，所述放射性核素包括选自由44Sc、47Sc、64Cu、67Cu、67Ga、68Ga、90Y、99mTc、111In、177Lu、188Re、212Pb、213Bi、211At、223Ra、和225Ac所组成的组中的至少一个或由其组成。在一些实施方式中，所述放射性核素包括选自由68Ga和177Lu所组成的组中的至少一个或由其组成。在一些实施方式中，所述放射性核素包括68Ga。在一些实施方式中，所述放射性核素包括177Lu。
在一些实施方式中，第三化合物和第一化合物反应得到第四化合物，是通过点击反应。
在一些实施方式中，获得第一化合物包括：R2环肽和双环[6.1.0]壬炔(BCN)–L2–N-羟基琥珀酰亚胺(NHS)反应得到第一化合物。在一些实施方式中，获得第二化合物包括：R1环肽的带有或不带有保护基的线性肽、带有或不带有保护基的L1-CH2CH2OH、带有或不带有保护基的赖氨酸、和DO3AtBu-N3反应得到第二化合物。在一些实施方式中，所述治疗为放射性治疗。
在一些实施方式中，本申请开发了新型白蛋白结合剂，能够显著增加肿瘤吸收，而不会对非肿瘤器官产生负面影响，从而提高治疗指数。
为更进一步阐述本申请为了达成预定目的所采取的技术手段及功效，以下结合附图及较佳实施例，对依据本申请的具体实施方式、结构、特征及其功效，详细说明如下。
实施例
本申请的实施例和比较例如表1所示，其中实施例L00作为比较例。
[表1]
其中以上提到的SEQ ID NO:1–6序列如表2所示。
[表2]
其中表述“c(……)”意指环肽，小写正体字母意指D-氨基酸，斜体“Sar”意指肌氨酸。
【实施例化合物的制备】
以下以实施例L11化合物为例，但不限于此。本领域技术人员应当理解，可以通过与以下合成实施例
L11化合物类似的方式对应地合成其他实施例的化合物，包括但不限于表1所示的实施例化合物。
在本文中，实施例L11可简称为“L11”，其余实施例依此类推。
1.制备前体R2-L2-BCN
1.1将46μL的N,N-二异丙基乙胺(DIEA)(278μmol)添加到溶有20mg的SEQ ID NO:3环肽(27.78μmol)和22.5mg的BCN-L2-NHS酯(41.7μmol)的100μL的N,N-二甲基甲酰胺(DMF)中。
1.2将反应混合物在室温下搅拌2小时。
1.3分离产物：使用高效液相色谱层析(HPLC)。固定相为半制备C18柱，流动相采用梯度洗脱法，流速为4mL/min，并在20分钟内从5％乙腈变为50％乙腈。
1.4鉴定产物：通过高效液相色谱和质谱分析。
1.5电喷雾质谱测定结果：m/z[M+H]+＝1144.87(化学式：C53H82N12O16，计算分子量1142.60)。电喷雾质谱图如图1，横轴为质荷比(m/z)，纵轴为相对强度(％)。
2.制备前体R1-L1-Lys-DOTA-N3
2.1.利用固相合成法合成线性肽Lys(Dde)-D-Phe-Asp(Otbu)-Gly-Arg(Pbf)(即，被保护的SEQ ID NO:1环肽的线性肽)，保持多肽链接在树脂上。
2.2用2％水合肼DMF溶液脱去第一个赖氨酸侧链的Dde保护基。
2.3用DMF洗涤树脂后，20％哌啶DMF溶液脱去最后一个精氨酸的Fmoc保护基。
2.4用DMF洗涤树脂后，固相合成法依次连接Fmoc-L1-CH2CH2OH、Fmoc-Lys(Boc)-OH、和DO3AtBu-N3。
2.5在DMF洗涤树脂后，用30％三氟乙醇的二氯甲烷溶液切割树脂2小时。过滤后，用旋蒸仪抽干溶剂，得到带有保护基的产物。
2.6将上一步骤产物用二氯甲烷溶解，苯并三唑-1-基-氧基三吡咯烷基鏻六氟磷酸盐(PyBop)两倍过量，DIEA十倍过量，45℃回流反应过夜。旋转蒸发仪旋去溶剂，得到环化产物。
2.7用95％的TFA裂解液脱去上步骤产物结构中的保护基团。
2.8将裂解液用氮气尽量吹干，加入乙醚析出产物。离心去除上清。沉淀用乙醚洗六次，然后常温挥干。
2.9分离产物：使用高效液相色谱层析。固定相为半制备C18柱，流动相采用梯度洗脱法，流速为4mL/min，并在20分钟内从5％乙腈变为50％乙腈。
2.10鉴定产物：通过高效液相色谱和质谱分析。
2.11电喷雾质谱测定结果：m/z[M+H]+＝1434.96(化学式：C62H103N19O20，计算分子量1433.76)。电喷雾质谱图如图2，横轴为质荷比(m/z)，纵轴为相对强度(％)。
3.制备前体R1-L1-Lys(-R3-H)-DOTA-N3
3.1称取20mg(13.94μmol)的R1-L1-Lys-DOTA-N3，溶于100μL的DMF中。
3.2依次向上步骤溶液中加入23μL的DIEA(139.4μmol)和11.5mg的-N*H2基团Boc保护的式(I′)化合物(20.89μmol)。
3.3将反应混合物在室温下搅拌2小时。
3.4用冰乙醚将上步骤产物沉淀。
3.5用95％TFA裂解液脱去上步骤产物中-R基团上的保护基。
3.6将裂解液用氮气尽量吹干，加入乙醚析出产物。离心去除上清。沉淀用乙醚洗六次，然后常温挥干。
3.7分离产物：使用高效液相色谱层析。固定相为半制备C18柱，流动相采用梯度洗脱法，流速为4mL/min，并在20分钟内从5％乙腈变为50％乙腈。
3.8鉴定产物：通过高效液相色谱和质谱分析。
3.9电喷雾质谱测定结果：m/z[M+2H]+＝832.25(化学式：C72H119N21O24，计算分子量1661.87)。电喷雾质谱图如图3，横轴为质荷比(m/z)，纵轴为相对强度(％)。
4.制备前体R1-L1-Lys(-R3-H)-DOTA-click-L2-R2
4.1分别称取15mg(9μmol)的R1-L1-Lys(-R3-H)-DOTA-N3和15mg(13.14μmol)的R2-L2-BCN，溶于100μL的DMF中。
4.2将反应混合物在室温下搅拌2小时。
4.3分离产物：使用高效液相色谱层析。固定相为半制备C18柱，流动相采用梯度洗脱法，流速为4mL/min，并在20分钟内从5％乙腈变为50％乙腈。
4.4鉴定产物：通过高效液相色谱和质谱分析。
4.5电喷雾质谱测定结果：m/z[M+2H]+＝1404.47(化学式：C125H201N33O40，计算分子量2804.47)。电喷雾质谱图如图4，横轴为质荷比(m/z)，纵轴为相对强度(％)。
5.制备R1-L1-Lys(-R3-R4)-DOTA-click-L2-R2缀合物
5.1称取12mg(4.28μmol)的R1-L1-Lys(-R3-H)-DOTA-click-L2-R2，溶于100μL的DMF中。
5.2依次向上步骤溶液中加入7μL的DIEA(42.8μmol)和5.6mg的式(III′)化合物(17μmol)。
5.3将反应混合物在室温下搅拌2小时。
5.4向反应混合物中加入1M的TFA水溶液，调节反应液pH至5.0–6.0。
5.5分离产物：使用高效液相色谱层析。固定相为半制备C18柱，流动相采用梯度洗脱法，流速为4mL/min，并在20分钟内从20％乙腈变为32％乙腈。
5.6鉴定产物：通过高效液相色谱和质谱分析。
5.7电喷雾质谱测定结果：m/z[M+2H]+＝1510.58(化学式：C136H210F3N33O41，计算分子量3018.53)。电喷雾质谱图如图5，横轴为质荷比(m/z)，纵轴为相对强度(％)。
【稳定性研究】
实验采用体外恒温(37℃)孵育法研究实施例L11化合物(1.0μg/mL)在小鼠血浆或PBS中的稳定性。实施例L11化合物溶解在1mL小鼠血清中，体外恒温孵育0h、0.5h、1h、4h、24h和48h，然后测定药物剩余百分率。采用PBS作为阴性对照组。采用LC-MS/MS法测定药物与内标的峰面积，用其比值代替药物浓度进行计算。
结果如表3。
[表3]实施例L11化合物在小鼠血浆或PBS中体外恒温孵育后的药物剩余百分率
可以看到，实施例L11化合物在小鼠血浆或PBS中体外恒温孵育后的药物剩余百分率基本保持在95％以上，说明其稳定性较高。
【动物实验】
1.人胰腺癌异种移植瘤模型构建
取BxPC3人胰腺癌细胞，于200μL磷酸盐缓冲液和基质凝胶(v/v，1/1)混合液中，植入2×106个细
胞于正常NCr裸鼠(18–25g，4–6周龄)左肩皮下。在平均1.5周之后，肿瘤直径约10mm，已经足以进行生物分布和SPECT/CT成像研究。
2.化合物的68Ga标记
2.1用1.0mL的0.25M醋酸钠溶液溶解1.0μmol的实施例L11化合物。
2.2采用4mL的0.05M盐酸溶液洗脱锗镓发生器，制备68GaCl3淋洗液。
2.3取1μmol的实施例L11化合物溶液，加入到中1mCi活度的淋洗液中，再加入300μL的0.25M醋酸钠溶液，60℃反应10min，获得68Ga-L11复合物。所得到的混合物，通过放射高效液相色谱进行监测和定量标记，纯度>97％。
3.小型动物的正电子发射型计算机断层显像(PET-CT)
PET-CT和图像分析使用小型动物NovelMedcal PET-CT扫描仪(北京永新)进行。其在视野中心的切向和径向半宽最大值为1.5mm，在视野边缘的切向和径向半宽最大值为1.8mm。
在异氟醚麻醉下，将约100μCi的68Ga-L00、68Ga-L11、68Ga-L12、68Ga-L13、和68Ga-L21复合物通过尾静脉注射至BxPC3荷瘤小鼠体内，每种复合物注射于4只小鼠中。静脉注射0.5、1、2、3、4、5和6小时后，分别获得15分钟的静态PET-CT图像。比较5种复合物在各时间点的现象效果。
PET和CT图像利用NMSoft工作站软件(北京永新)进行采集，数据以每克组织或器官的注射剂量百分比(ID/g)给出，并通过每个样本的衰变校正(标准化到代表注射剂量的已知重量)来确定。统计时进行归一化，标准化摄取值(SUVs)根据以下公式计算：
SUV＝([Bq/mL]×[动物体重(g)]/[注射剂量(Bq)])
5种复合物在各时间点的肿瘤、肌肉、和肾脏的摄取如图6和图7所示。
对于缀合物结构中无白蛋白结合片段的实施例L00缀合物形成的68Ga-L00复合物，注射后2小时内，药物快速经肾代谢，肿瘤组织处信号逐渐减弱，2小时后的肿瘤/肾脏比值仅有约0.18。
其余4个复合物注射后，短时间内小鼠周身血池均能检测到信号，证明复合物中的白蛋白结合片段发挥了作用，增加了复合物的体内循环时间。并且，随着时间的增加，大部分复合物经肾随尿液排出，周身正常组织处的背景信号逐渐降低，但肿瘤组织处信号逐渐增强，提示复合物在肿瘤组织处随时间呈现特异性富集。
其中实施例L11化合物形成的68Ga-L11复合物在注射6小时后，肿瘤/肾脏比值能够达到1.4左右，且有继续增大的趋势，表明实施例L11化合物具有较好的稳定性、靶向性和特异性。
68Ga-L12复合物注射后，显像的整体趋势与68Ga-L11复合物相似，但5–6小时肿瘤组织处的蓄积不如68Ga-L11复合物明显。
68Ga-L13复合物也表现出了类似的趋势，但肿瘤组织的整体摄取率小于68Ga-L11复合物。
对于68Ga-L21复合物，因实施例L21缀合物在结构中关键的多肽靶头和白蛋白结合片段与实施例L21缀合物均相同，仅有一处连接子结构不同，因此其二者的组织分布趋势和程度很类似。
图7的A展示了各复合物组各选择一只代表性动物，展示药物注射5小时后的体内分布情况。
从MIP图和肿瘤、肾脏、肌肉ROI区域定量结果显示，68Ga-L11复合物的肿瘤/肾脏比值和肿瘤/肌肉比值在5个缀合物中是最高的，但对比68Ga-L00复合物，其余4个复合物的体内稳定性和肿瘤组织蓄积都有显著提升。
4.实施例L11化合物的177Lu标记
将6μL的0.5nmol/μL实施例L11化合物溶液添加到1mCi的177LuCl3中，缓冲液为200μL的0.1M醋酸–醋酸铵缓冲液(pH＝3.7–4.0)，然后在90℃下加热15分钟。
所得到的混合物，通过放射高效液相色谱进行监测和定量标记(>97％)，可获得177Lu-L11复合物。
5.小型动物的单光子发射型计算机断层显像(SPECT-CT)
SPECT-CT和图像分析使用小型动物NovelMedcal SPECT-CT扫描仪(北京永新)进行。其在视野中心的切向和径向半宽最大值为1.5mm，在视野边缘的切向和径向半宽最大值为1.8mm。
在异氟醚麻醉下，将约500μCi的177Lu-L11复合物通过尾静脉注射至BxPC3荷瘤小鼠体内，共注射4只动物。静脉注射4、24、48、72和96小时后，分别获得30分钟的静态SPECT-CT图像。评价177Lu-L11复合物长时间点现象效果。
SPECT-CT成像结果如图8所示。静脉注射177Lu-L11溶液4天时间内，小鼠肿瘤组织处能持续检测到放射信号，且其他组织器官处已无信号，提示实施例L11化合物具有较好的体内稳定性和靶向性，具备与长半衰期的治疗性核素177Lu配合，用于肿瘤的放射性治疗的潜力。
6.生物分布研究
将实施例的177Lu-L11、177Lu-L12、177Lu-D-L11、177Lu-L11-1复合物(3.7MBq)静脉注射到BxPC3荷瘤NCr裸鼠中，于给药后1、4、24、48、72、和120小时的各个时间点对5只鼠安乐死，死后解剖取材。
采集感兴趣的组织和器官，用γ计数器进行加权和放射性计数。
图9示出了177Lu-L11、177Lu-L12、177Lu-D-L11、177Lu-L11-1四种复合物静脉注射24小时后小鼠各组织放射性分布情况。其中，纵轴数值以每克组织或器官的注射剂量百分比(ID/g)给出，并通过每个样本的衰变校正(标准化到代表注射剂量的已知重量)来确定。
由图9可以看到，静脉注射24小时后，177Lu-L11、177Lu-L12、177Lu-D-L11、177Lu-L11-1四种复合物都会在肿瘤中富集，其中177Lu-L12的富集程度高于其他三个。此外，这些复合物在肾脏也有一定的富集，脾脏与子宫等有较少量的富集。
7.统计分析
采用graphpad6中双侧非配对t检验进行统计分析。概率(p)值小于0.05为有统计学意义。
上述实施方式仅为本申请的优选实施方式，不能以此来限定本申请保护的范围，本领域的技术人员在本申请的基础上所做的任何非实质性的变化及替换均属于本申请所要求保护的范围。
Claims (10)
- 一种化合物，其特征在于，包括式(A)结构，
其中，所述Z1为–L1R1或–H，所述Z2为–L2R2或–H，条件是所述Z1为–L1R1且/或所述Z2为–L2R2；所述L1为–(PEG)m–，且所述m为选自4至30之间的整数；所述L2为–(PEG)n–，且所述n为选自4至30之间的整数；所述R1包括由精氨酸、甘氨酸或肌氨酸、和天冬氨酸依序连接的肽；所述R2包括由天冬酰胺、甘氨酸或肌氨酸、半胱氨酸、和精氨酸依序连接的肽；所述R3为式(I)基团或式(II)基团，
所述R4为式(III)基团、式(IV)基团或长链脂肪酸，
所述Q1、所述Q2、所述Q3、所述Q4、和所述Q5各自独立地选自由-H、-F、-Cl、-Br、-I、C1–C6直链或支链烷基、C1–C6直链或支链氟烷基、和C1–C6直链或支链氟烷氧基所组成的组；所述x为选自由1、2、3、4、5、6、7、和8所组成的组的整数；且所述y为选自由1、2、3、4、5、和6所组成的组的整数。 - 如权利要求1所述的化合物，其特征在于，所述Z1为–L1R1且所述Z2为–L2R2；且/或所述m为4；且/或所述n为4。
- 如权利要求1或2所述的化合物，其特征在于，所述x为3；且/或所述R4为式(III)基团，且所述y为2或3。
- 如权利要求1至3任一所述的化合物，其特征在于，所述R4为式(III)基团；且所述Q1为-H；所述Q2为-H；所述Q3为选自由-H、-F、-Cl、-Br、-I、-CH2F、-CHF2、和-CF3所组成的组；所述Q4为-H或-F；且/或所述Q5为-H或-F；可选地，所述Q1为-H；所述Q2为-H；所述Q3为-CF3；所述Q4为-H或-F；且/或所述Q5为-H或-F可选地，所述Q1为-H；所述Q2为-H；所述Q3为-CF3；所述Q4为-H或-F；且所述Q5为-H或-F。
- 如权利要求1至4任一所述的化合物，其特征在于，所述R1为环肽且还包括賴氨酸；可选地，所述R1为包括由L-精氨酸、甘氨酸或肌氨酸、和L-天冬氨酸依序连接的三肽序列，和L-赖氨酸，的环肽；可选地，所述R1为由4至7个氨基酸组成的环肽；可选地，所述R1为由5个氨基酸组成的环肽；可选地，所述R1为SEQ ID NO:1–2任一所示的环肽；且/或所述R2为环肽且还包括賴氨酸；可选地，所述R2包括由L-天冬酰胺、甘氨酸或肌氨酸、和L-精氨酸依序连接的三肽序列，和L-赖氨酸，的环肽；可选地，所述R2为由4至7个氨基酸组成的环肽；可选地，所述R2为由5或6个氨基酸组成的环肽；可选地，所述R2为SEQ ID NO:3–6任一所示的环肽。
- 权利要求1至5任一所述的化合物在放射性核素标记或制备放射性核素标记试剂中的用途。
- 一种放射性核素制剂，其特征在于，包括：如权利要求1至3任一所述的化合物；以及放射性核素，与所述化合物螯合。
- 如权利要求7所述的放射性核素制剂，其特征在于，所述放射性核素包括选自由44Sc、47Sc、62Cu、64Cu、67Cu、66Ga、67Ga、68Ga、86Y、90Y、89Zr、99mTc、110mIn、111In、113mIn、114mIn、177Lu、188Re、203Pb、212Pb、212Bi、213Bi、211At、223Ra、和225Ac所组成的组中的至少一个；可选地，所述放射性核素包括选自由44Sc、47Sc、64Cu、67Cu、67Ga、68Ga、90Y、99mTc、111In、177Lu、188Re、212Pb、213Bi、211At、223Ra、和225Ac所组成的组中的至少一个；可选地，所述放射性核素包括68Ga或177Lu。
- 权利要求1至6任一所述的化合物或权利要求7或8所述的放射性核素制剂的制备方法，其特征在于，包括：获得包括式(A1)结构的第一化合物，
获得包括式(A2)结构的第二化合物，
所述第二化合物的-N*H2基团与式(I′)化合物或式(II′)化合物或其-N*H2基团保护的化合物的-C*OOH基团形成酰胺键，得到包括式(I″)基团或式(II″)基团的第三化合物，
所述第三化合物和所述第一化合物反应得到第四化合物；以及将所述第四化合物的所述式(I″)基团或所述式(II″)基团的-N*H2基团与式(III′)化合物的-C*OOH基团形成酰胺键，
- 如权利要求1至5任一所述的化合物、或如权利要求7至8任一所述的放射性核素制剂，在制备检测癌症、诊断癌症、监控癌症进展、监控癌症治疗或治疗癌症的药物中的用途。
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