Zwitterionic metal chelators

Abstract

The present invention relates to zwitterionic metal chelators and their use as imaging agents, diagnostic agents, chemical processing agents, and therapeutic agents. These zwitterionic metal chelators have desirable properties of maximizing solubility in aqueous environments, minimizing non-specific interactions, and retaining targeting ability, resulting in improved performance in a variety of medical, agricultural, and chemical processes. In vivo and medical applications, the zwitterionic metal chelators improve signal-to-background ratios and therapeutic windows compared to other metal chelators, while retaining high stability.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 538,038, filed September 12, 2023; U.S. Utility Patent Application Serial No. 18 / 640,169, filed April 19, 2024; and U.S. Utility Patent Application Serial No. 18 / 732,982, filed June 4, 2024. The disclosure of each of these applications is incorporated herein by reference.

[0003] This application also relates to U.S. Utility Patent Application Serial No. 18 / 641,097, filed April 19, 2024; U.S. Utility Patent Application Serial No. 18 / 641,149, filed April 19, 2024; U.S. Utility Patent Application Serial No. 18 / 641,620, filed April 19, 2024; U.S. Provisional Patent Application Serial No. 63 / 648,302, filed May 16, 2024; and U.S. Provisional Patent Application Serial No. 63 / 656,858, filed June 6, 2024. The disclosure of each of these applications is incorporated herein by reference.

[0004] sequence list

[0005] The sequence list conforming to WIPO standard ST.26 is incorporated herein by reference. The sequence list was submitted as an electronic document in UTF-8 text encoding as XML via PatentCenter. This electronic document, created on September 7, 2024, is named “1515138_105WO2_SL.xml” and has a size of 6,237 bytes. Technical Field

[0006] This invention relates to zwitterionic metal chelators and their use as imaging agents, diagnostic agents, chemical processing agents, and therapeutic agents. These zwitterionic metal chelators possess desirable properties: maximizing solubility in aqueous environments, minimizing nonspecific interactions, and retaining targeting capabilities, thereby leading to improved performance in a variety of medical, agricultural, and chemical processes. In in vivo and medical applications, zwitterionic metal chelators improve the signal-to-background ratio and therapeutic window compared to other metal chelators, while maintaining high stability. Background Technology

[0007] Cationic metals are insoluble in water. For this reason, whenever they are needed in medical, agricultural, or chemical processes, they must be bound to organic compounds, for example, through coordination or chelation, so that the complex is soluble in an aqueous environment and has low toxicity. The previously described metal chelating agents have rarely addressed the polyionicity and sphere of hydration required for complete metal separation, thus leading to undesirable nonspecific interactions.

[0008] Chelated metals are commonly used in a variety of current imaging techniques. These techniques, such as magnetic resonance imaging (MRI), single-photon emission computed tomography (SPECT), or positron emission tomography (PET), allow for the detection of diseases at the cellular level. These imaging techniques rely on isotopes of Gd, Mn, Cu, Ga, Zr, Eu, Tc, and many other metals—many of which are radioactive. Additionally, isotopes of Cu, Lu, Ac, Pb, Bi, Y, Sc, Tb, Ra, Gd, etc., are commonly used in therapeutic applications such as radiotherapy and neutron capture therapy.

[0009] However, in the aforementioned applications, metal isotopes need to be bound to metal chelators to prevent toxicity and maintain association with the target carrier. Many common metal chelators, such as DOTA, PyC3A, and macropa, lack the ability to modulate pharmacokinetics, solubility, nonspecific tissue / organ uptake, and plasma-protein binding. Furthermore, common metal chelators are not easily cleared from the body, leading to accumulation in off-target tissues and organs. For diagnostic imaging, this results in high background noise. For radiotherapy, it leads to toxicity without any benefit.

[0010] Similarly, in any agricultural or chemical process requiring metal chelation, little attention is currently paid to the level of aqueous solubility achieved or the mechanisms that minimize nonspecific interactions that reduce process yields or fail to block side reactions.

[0011] Several studies have been conducted to provide derivatives of these chelating agents by allowing conjugation of targeting carriers such as antibodies, peptides, small molecules, and steroids. These derivatives are typically produced by replacing one or more carboxylic acid arms of the chelating agent to include the targeting carrier. However, such substitutions often have a significant impact on the chelating properties of the chelating agent—making their metal-binding properties poorer, if not entirely useless for biomedical applications. In some cases, the substitutions alter the biodistribution and / or clearance of the molecule, which may result in higher background or a smaller therapeutic window.

[0012] Therefore, there remains a need for new and improved reagents with high stability that maximize the solubility of metal complexes in aqueous environments, minimize nonspecific / off-target interactions, rapidly equilibrate between intravascular and extravascular spaces upon injection, and are subsequently efficiently cleared from the body, including through renal filtration. The zwitterionic metal chelating agents of the present invention address these and other needs. Summary of the Invention

[0013] This invention provides zwitterionic metal chelators that can be used in a variety of medical, agricultural, and chemical processes. These chelators offer improved properties, such as high solubility in aqueous environments and low nonspecific interactions. When used in medical applications, they can improve the signal-to-background ratio of the imaged tissue and the therapeutic window of the treated tissue, while allowing for easier and more effective removal by the target.

[0014] In one aspect, this disclosure provides a zwitterionic metal chelating agent complex comprising a metal chelating agent having one or more zwitterionic groups and a metal or metal isotope selected from radionuclides, labeled, paramagnetic metals and heavy metals.

[0015] In some embodiments, the metal chelating agent is a derivative of DOTA, deferoxamine, NOA, PyC3A, macropa, or porphyrin. In other embodiments, the zwitterionic metal chelating agent complex further comprises one or more targeting carriers. In some specific embodiments, one or more targeting carriers are cRGD, PSMA-617, FAPI, octreotide, bombesin, or homodimers or heterodimers formed by combinations thereof.

[0016] In some implementations, the metal chelating agent is a derivative of DOTA, and the metal or metal isotope is Pb, Zr, Cu, Ga, In, Y, Gd, Lu, Ac, or Tb.

[0017] In other embodiments, the metal chelating agent is PyC3A, and the metal or metal isotope is Mn.

[0018] In other embodiments, the metal chelating agent is macropa, and the metal or metal isotope is Ac. 3+ Or Bi 3 + .

[0019] In some other embodiments, the metal chelating agent is a derivative of NOA, and the metal or metal isotope is Ga. 3 + Cu 2+ Gd 3+ Ac 3+ Or Bi 3+ .

[0020] In other embodiments, the metal chelating agent is a derivative of desferrioxamine, and the metal or metal isotope is Zr. 4+ Fe 3+ Mn 2+ or Mn 3+ .

[0021] In other embodiments, the metal chelating agent is a porphyrin derivative, and the metal or metal isotope is Mn. 2 + Mn 3+ Fe 2+ Fe 3+ Gd 3+ Ac 3+ Or Bi 3+ .

[0022] In some embodiments, the zwitterionic metal chelating agent in the zwitterionic metal chelating agent complex has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group.

[0023] In other embodiments, the zwitterionic metal chelating agent in the zwitterionic metal chelating agent complex has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group.

[0024] In other embodiments, the zwitterionic metal chelating agent in the zwitterionic metal chelating agent complex has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group.

[0025] In some other embodiments, the zwitterionic metal chelating agent in the zwitterionic metal chelating agent complex has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group.

[0026] In other embodiments, the zwitterionic metal chelating agent in the zwitterionic metal chelating agent complex has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group.

[0027] In some other embodiments, the zwitterionic metal chelating agent in the zwitterionic metal chelating agent complex has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group.

[0028] In other embodiments, the metal chelating agent is PyC3A, and the metal or metal isotope is Mn.

[0029] In some embodiments, the metal chelating agent is a derivative of DOTAM. In other embodiments, the zwitterionic metal chelating agent complex further comprises one or more targeting carriers. In some specific embodiments, one or more targeting carriers are cRGD, PSMA-617, FAPI, octreotide, bufotalin, or homodimers or heterodimers formed by combinations thereof.

[0030] In some embodiments, the metal chelating agent is a derivative of DOTAM, and the metal or metal isotope is Pb, Pd, Zr, Cu, Ga, In, Y, Gd, Lu, Ac, or Tb.

[0031] In some embodiments, the zwitterionic metal chelating agent in the zwitterionic metal chelating agent complex has the following formula: Where ZWI represents a zwitterionic group; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group. The substituent R is hydrogen or alkyl or a combination of both.

[0032] In another aspect, this disclosure provides a developer comprising a zwitterionic metal chelating agent complex according to this disclosure.

[0033] In another aspect, this disclosure provides a method for imaging cells, tissues, or organs, the method comprising:

[0034] (a) Contacting cells with an imaging agent according to this disclosure; and

[0035] (b) Imaging cells, tissues or organs using positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI).

[0036] In some implementations of the imaging method, the cells are tumor cells or cells undergoing angiogenesis.

[0037] In other embodiments of the imaging method, the imaging agent is applied to an organism that contains or is suspected of containing the cells.

[0038] In some specific implementations of the imaging method, the organism is a human being.

[0039] In some implementations of the imaging method, tissues or cells are imaged in vivo.

[0040] In another aspect, this disclosure provides therapeutic agents comprising a zwitterionic metal chelating agent complex according to this disclosure, and a pharmaceutically acceptable carrier or excipient.

[0041] In another aspect, this disclosure provides a method for treating cancerous conditions in subjects with this need, the method comprising:

[0042] The cancer cells of the subject are brought into contact with an effective amount of the therapeutic agent according to this disclosure.

[0043] The metal atoms that combine with the zwitterionic metal chelating agent are:

[0044] A known radioactive metallic isotope emits ionizing radiation, which causes cell death upon ingestion of the analogue.

[0045] Or non-radioactive metals that can release cytotoxic radiation after irradiation with alpha radiation, beta radiation, neutron capture, or a combination thereof.

[0046] In some embodiments of the treatment method, the metal atom complexed with the zwitterionic metal chelator is a non-radioactive metal capable of releasing cytotoxic radiation after irradiation with alpha radiation, beta radiation, neutron capture, or a combination thereof; the method also includes the step of irradiating tumor cells with alpha radiation, beta radiation, neutron capture, or a combination thereof.

[0047] In some other implementations of the treatment, the cancer cells are adult solid tumor cells or pediatric solid tumor cells.

[0048] In other implementations of the treatment, the cancer cells are melanoma cells, neuroblastoma cells, lung cancer cells, adrenal cancer cells, colon cancer cells, colorectal cancer cells, ovarian cancer cells, prostate cancer cells, liver cancer cells, subcutaneous cancer cells, squamous cell carcinoma cells, colon cancer cells, retinoblastoma cells, cervical cancer cells, glioma cells, breast cancer cells, pancreatic cancer cells, Ewings sarcoma cells, rhabdomyosarcoma cells, osteosarcoma cells, retinoblastoma cells, Wilms' tumor cells, and pediatric brain tumor cells.

[0049] In some embodiments of the treatment, the cancer cells are prostate cancer cells. In other embodiments, the cancer cells are malignant cancer cells.

[0050] In another aspect, this disclosure provides a method for treating non-cancerous conditions in subjects with this need, the method comprising:

[0051] Administering an effective amount of the therapeutic agent according to this disclosure to the subject.

[0052] The metal atoms that combine with the zwitterionic metal chelating agent are:

[0053] A known radioactive metallic isotope emits ionizing radiation, which results in a therapeutic effect on the target.

[0054] Or a non-radioactive metal that can release therapeutic radiation after irradiation with alpha radiation, beta radiation, neutron capture, or a combination thereof.

[0055] In some implementations of the treatment, the non-cancerous condition is a musculoskeletal disorder or a tissue hypertrophy disorder.

[0056] In some implementations of the treatment method, the target is a person.

[0057] In another aspect, this disclosure provides diagnostic agents comprising zwitterionic metal chelating complexes according to this disclosure, and pharmaceutically acceptable carriers or excipients.

[0058] In another aspect, this disclosure provides a method for measuring the potency of a biological system containing an object, the method comprising:

[0059] (a) Administering a quantifiable amount of the diagnostic agent according to this disclosure to the subject;

[0060] (b) Imaging the subject using positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); and

[0061] (c) Determine the amount of therapeutic agent present in the biological system observed in the subject.

[0062] In some implementations of methods for measuring the efficacy of biological systems, the biological system is the renal system, the hepatic system, or a blood pool.

[0063] In another aspect, this disclosure provides a method for measuring the efficacy of renal function in a subject, the method comprising:

[0064] (a) Administering a quantifiable amount of the diagnostic agent according to this disclosure to the subject;

[0065] (b) Imaging the subject using positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); and

[0066] (c) Determine the amount of therapeutic agent present in the biological system observed in the subject.

[0067] In another aspect, this disclosure provides a method for quantifying the glomerular filtration rate of a subject, the method comprising:

[0068] (a) Administering a quantifiable amount of the diagnostic agent according to this disclosure to the subject;

[0069] (b) Using measurements of each bodily fluid or imaging the subject with positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI), determine the amount of diagnostic agent present in the subject's blood and urine as a function of time.

[0070] In another aspect, this disclosure provides a method for removing toxic or excessive metals from an object requiring such treatment, the method comprising:

[0071] (a) Administering a therapeutically effective amount of the therapeutic agent according to this disclosure to the subject.

[0072] The therapeutic agent comprises a metal chelating agent having one or more zwitterionic groups not coordinated with a metal or metal isotope, and a pharmaceutically acceptable carrier or excipient.

[0073] In some embodiments of methods for removing toxic or excessive metals from an object, the metal chelating agent in the therapeutic agent has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group.

[0074] In other embodiments of the method for removing toxic or excessive metals from an object, the toxic or excessive metals are lead, mercury, arsenic, cadmium, thallium, iron, zinc, chromium, manganese, aluminum, cobalt, selenium, beryllium, lithium, silver, or tin.

[0075] In another aspect, this disclosure provides a radiosurgical method for treating a patient's body, the method comprising:

[0076] Receive the desired lesion pattern and planned radiation distribution;

[0077] Administering an effective amount of the diagnostic agent according to this disclosure to the subject to effectively image the desired lesion pattern;

[0078] To treat the patient's body by performing surgery on the desired lesion pattern.

[0079] In some embodiments of the radiosurgical methods described in this disclosure, the zwitterionic metal chelating agent of the diagnostic agent further comprises one or more targeting carriers.

[0080] The one or more targeting vectors are cRGD, PSMA-617, FAPI, octreotide, bufotoxin, or homodimers or heterodimers formed by combinations thereof.

[0081] In some other embodiments of the radiosurgery method of this disclosure, the desired lesion pattern is received from the user interface of the treatment planning module.

[0082] In other embodiments of the radiosurgery method disclosed herein, the treatment planning module is pre-programmed with instructions for various disease states and cancerous conditions.

[0083] In some further embodiments of the radiosurgery methods disclosed herein, the treatment planning module uses artificial intelligence data to identify lesion patterns for a variety of disease states and cancerous conditions.

[0084] In some specific embodiments of the radiosurgery methods disclosed herein, the surgery is performed using a stereotactic radiosurgery system.

[0085] In another aspect, this disclosure provides a method for treating cancer by administering an effective amount of a therapeutic agent according to this disclosure, wherein the method includes the steps of diagnosing cancer and administering the therapeutic agent to a subject determined to have such a need.

[0086] The steps involved in diagnosing cancer include:

[0087] To bring the subject's cells, tissues, or organs into contact with the imaging agent.

[0088] Using positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI) to image the cells, tissues, or organs of a subject, and

[0089] Diagnostic methods for cancer in the cells, tissues, or organs of a subject based on the collected imaging data;

[0090] Furthermore, the metal atoms that are complexed with the zwitterionic metal chelating agent are:

[0091] A known radioactive metallic isotope emits ionizing radiation, which causes cell death upon ingestion of the analogue.

[0092] Or non-radioactive metals that can release cytotoxic radiation after irradiation with alpha radiation, beta radiation, neutron capture, or a combination thereof. Attached Figure Description

[0093] Figure 1 This is an illustration of seven non-targeted zwitterionic metal chelating agents according to the present invention.

[0094] Figure 2 This is an illustration of seven targeted zwitterionic metal chelators according to the present invention (targeting vector = tv).

[0095] Figure 3 This is a diagram of the zwitterionic group according to the present invention.

[0096] Figure 4 These are illustrations of three target carriers covered by this invention.

[0097] Figure 5 This is a diagram illustrating the synthesis of zwitterionic conjugates based on DOTA (Scheme 2).

[0098] Figure 6 This is a diagram illustrating the synthesis of zwitterionic conjugates based on deferoxamine (Scheme 7). Detailed Implementation

[0099] This disclosure relates in particular to imaging agents, diagnostic agents, therapeutic agents, or chemical agents composed of zwitterionic metal chelators. In some aspects, the reagents described herein can be used, for example, for the detection of abnormal or diseased biological tissues and cells. In some aspects, zwitterionic metal chelators are particularly useful for imaging the whole organism because they exhibit improved in vivo behavior, such as low nonspecific binding to non-target tissues and high stability, resulting in improved signal-to-background ratio and / or improved therapeutic window associated with the detected signal. Similarly, in agricultural or chemical processes currently using metal chelators, zwitterionic metal chelators improve solubility and minimize nonspecific interactions. These improved properties are thought to arise from the balance of formal charges on the metal chelator, resulting in multi-ionic but “charge-balanced” molecules with a neutral or near-neutral net charge, an expanded hydration layer, and better metal separation.

[0100] Definitions and alternative implementation schemes

[0101] The following definitions will be used to understand this invention.

[0102] The term “comprising / including” as used herein is intended to mean that a composition and method includes the elements described, but does not exclude other elements. “consistently composed of” when used to define a composition and method should mean excluding other elements that have any substantial significance to the composition. Therefore, a composition consisting substantially of the elements as defined herein does not exclude trace contaminants from separation and purification methods, and pharmaceutically acceptable carriers, such as phosphate-buffered saline, preservatives, etc. “consisting of” should mean excluding other components and elements exceeding trace amounts in substantial method steps for administering the compositions of the invention. Embodiments defined by each of these transitional terms are within the scope of the invention.

[0103] Unless the context clearly specifies otherwise, nouns not limited by quantifiers used in this specification and claims include plural references.

[0104] The ranges provided in this document should be understood as abbreviations of all values ​​within that range. For example, the range 1 to 50 is understood to include any number, combination of numbers, or subrange from the following: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50.

[0105] Unless otherwise specified or obvious from the context, the term “or” as used herein shall be understood as inclusive.

[0106] The inclusion of a chemical group in any definition of a variable herein includes any single group or combination thereof that defines the variable as one of the listed groups. Descriptions of embodiments of a variable or aspect herein include embodiments as any single embodiment or in combination with any other embodiment or part thereof.

[0107] The terms “object” or “patient” as used in this article encompass both mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, cattle, horses, sheep, goats, pigs; rabbits, dogs, cats, rats, mice, guinea pigs, etc. Examples of non-mammals include, but are not limited to, birds, fish, parasites, microorganisms, etc.

[0108] As used herein, the term "administering" a compound to a subject refers to providing the zwitterionic metal chelating agent and / or its precursor drug of the present invention to a subject requiring diagnosis or treatment.

[0109] As used herein, the terms "targeting carrier" or "targeting ligand" refer to the portion that binds to or coordinates with the zwitterionic metal chelator of the present invention to provide enhanced binding or increased concentration to a specific cell type in the presence of that cell type. In some embodiments, the targeting carrier may bind to the zwitterionic metal chelator in addition to the zwitterionic group. In other embodiments, the targeting carrier may replace one or more zwitterionic groups when binding to the zwitterionic metal chelator, provided that the zwitterionic metal chelator retains at least one zwitterionic group.

[0110] As used herein, the terms "therapeutic window" or "therapeutic index" refer to the relationship between a therapeutic dose and a toxic dose of a given drug, and are calculated using ED50 and TD50 (therapeutic index = TD50 / ED50). In some embodiments of the invention, the zwitterionic metal chelating agent of the present invention has a higher therapeutic index relative to other metal chelating agents. In some other embodiments, the therapeutic window refers to what is defined herein as [TD1 / ED50]. 99 The CSF is the certainty safety factor (CSF) of the ratio of [1 / 100] to [1 / 100]. A CSF > 1 indicates that the effective dose in 99% of the population is less than the toxic dose in 1% of the population. In some embodiments of the invention, the zwitterionic metal chelating agent of the present invention has a higher CSF than other metal chelating agents.

[0111] As used in this article, the term "carrier" refers to a chemical compound or reagent that facilitates the incorporation of the compounds described herein into cells or tissues.

[0112] The term “acceptable” as used herein with respect to formulations, compositions or ingredients as used herein means that there is no persistent harmful effect on the overall health of the person being treated.

[0113] As used herein, the term "diluent" refers to a chemical compound used to dilute the compounds described herein prior to delivery. Diluents may also be used to stabilize the compounds described herein.

[0114] As used herein, the terms "zwitterionic group," "zwitterionic ligand," or "zwitterion" refer to one or more charged portions or ligands present on or capable of reacting with the metal chelating agent nucleus. The zwitterionic metal chelating agent of the claimed invention is composed of one or more zwitterionic groups (i.e., positively charged (A+, ...) groups). Figure 3 ) and negative charge (B-, Figure 3 The zwitterionic groups are modified to have a total net charge of zero. These zwitterionic groups differ from the chelating core itself, which typically has a negative charge to chelate positively charged metals. For example, a zwitterionic metal chelate with a -4 chelating core that binds a +4 metal has a total net charge of zero. Although a total net charge of zero is considered ideal, zwitterionic metal chelates with a -4 chelating core that binds a +2 metal, resulting in a total charge of -2, are still expected to exhibit improved properties in vivo because the chelating core / metal complex is masked by one or more zwitterionic groups. In the absence of zwitterionic groups, the molecule does not have such masking or expanded hydration and is more likely to undergo nonspecific binding.

[0115] A particular active agent molecule may have several linked "zwitterionic groups" or charge pairs. Generally, the anionic and cationic portions of a zwitterionic group (charge pair) are part of the same moiety, but the two ionic groups can interact to form a separate portion of the zwitterionic group. In some specific embodiments, the zwitterionic group is covalently bonded to the base structure via carbon-carbon, carbon-oxygen, or nitrogen-carbon bonds. Some examples of zwitterionic groups (charge pairs) that may be included in the compounds and complexes of the claimed invention include, but are not limited to, ammonium phosphate, ammonium phosphonate, ammonium phosphine sulfate, ammonium sulfonate, ammonium carboxylate, ammonium sulfonamide, ammonium sulfone imide, guanidiniocarboxylate, pyridylcarboxylate, pyridylsulfonate, ammonium (alkoxy)dicyanoethylene alcohol, ammonium borate, sulfonylcarboxylate, phophoniosulfonate, and phosphonocarboxylate. The charged groups in these zwitterions can be separated by suitable spacer groups ( Figure 3The zwitterion is separated by a C), such as a straight or branched alkyl chain, aryl or heteroaryl moiety. In some embodiments, the zwitterion group can be a derivative of an amino acid, such as aminocarboxylic acid, aminophosphonic acid, aminophosphinolic acid, or aminosulfonic acid, as well as sulfates / esters or phosphates / esters substituted with aminoalkyl groups. The zwitterion can also be a derivative of betaine, such as carboxybetaine, sulfobetaine, sulfabetaine, phosphonate betaine, or phosphate betaine, or an N-oxide, or a derivative of aminosulfonic acid. Some specific examples of zwitterions include ammonium sulfobetaine or N-oxides. A simple example of a zwitterion group at physiological pH is a charge pair of a carboxylic acid (deprotonated at physiological pH) and an amine (protonated at physiological pH).

[0116] In some embodiments, the zwitterionic metal chelating agent of the present invention may further comprise a targeting carrier for agricultural processes, chemical processes, diseases, or tissue-specific epitopes, such as a cyclic peptide cRGDyK (also known as cRGD), which binds to one or more arms of the metal chelating agent. Figure 4 cRGD is a cyclic derivative of the tripeptide Arg-Gly-Asp, which can be conjugated to one or more arms of the metal chelating agent of the present invention. In other embodiments, the targeting carrier is octreotide or bufotoxin. In other embodiments, the targeting carrier is KUE or dPSMA-617, a small molecule (also known as a FAP inhibitor or FAPI) capable of targeting fibroblast activation protein (FAP), an amino acid or combination of amino acids, or a derivative thereof. In such embodiments, a targeting carrier conjugate can be formed in place of one or more zwitterionic groups. In some embodiments, the targeting ligand comprises one or more of the following: having The LyP-1 peptide, which contains the sequence and binds to P32, is used for the diagnosis / treatment of melanoma; it has... The K237 peptide, which contains the sequence and binds to VEGFR-2, is used for the diagnosis / treatment of breast tumors; it has The IL4RPep-1 peptide, which contains the sequence of IL4R and binds to IL4R, is used for the diagnosis / treatment of lung cancer, breast cancer, and colon cancer; it has... The sequence of mUNO peptide, which binds to CD206, is used for the diagnosis / treatment of breast tumors; the folic acid receptor, used for the diagnosis / treatment of ovarian and lung cancer; and the dodecapeptide GE11, which binds to the epidermal growth factor receptor (EGFR or ErbB1), is used for the diagnosis / treatment of epithelial tumors.

[0117] Ideally, a zwitterionic metal chelates conjugated with a target carrier will utilize the total net charge of the target carrier. This is intentional because, in most cases, the charge on the target carrier is crucial for its ability to bind to its target. Therefore, targeted zwitterionic metal chelates retain the key advantage of maximizing specific binding while minimizing non-specific binding. It will be apparent to those skilled in the art that additional charge can be added to the zwitterionic metal chelate, if desired, to balance the total surface charge to zero.

[0118] In some embodiments, the zwitterionic metal chelating agent of the chelating agent of the present invention comprises a reactive linking group. Such a reactive linking group is typically an activated carboxylic acid derivative, such as n-hydroxysuccinimide (NHS) ester, sulfonated NHS ester, pentafluorophenyl (PFP) ester, hydroxybenzotriazole (HOBt) ester, hydroxyazabenzotriazole (HOAt) ester, tetrafluorophenyl (TFP) ester, acid anhydride, acid azide, or acid halide. As will be understood by those skilled in the art in synthesizing such compounds, such a reactive linking group can be attached to or substituted onto the chelating agent at any suitable structural position. The reactive linking group also includes, but is not limited to, alkynes, azides, maleimides, thiols, amines, alcohols, phenols, carbonyl groups, phosphines, alkenes, and tetraazines.

[0119] As used herein, the term "contact" refers to bringing substances together in a manner that allows them to interact with each other. For example, when a reagent is "contacted" with a tissue or cell, the tissue or cell can interact with the reagent, for example, allowing the possibility of binding interactions between the reagent and the molecular components of the tissue or cell. "Contact" also implies the administration of a substance, such as the reagent of the present invention, to an organism. Administration can be, for example, oral or extragastric.

[0120] As used herein, the term "ionic group" refers to a portion containing one or more charged substituents. A "charged substituent" is a functional group that is typically an anionic or cationic when in substantially neutral aqueous conditions (e.g., pH 6.5 to 8.0 or approximately physiological pH (7.4)). Some examples of charged anionic substituents, as listed above, include anions of inorganic and organic acids, such as sulfonates (-SO3-). 1-), oxides, sulfite ions, carboxyl ions, phosphonates, phosphonates, phosphate ions, and their esters (e.g., alkyl esters). In some embodiments, the charged substituents are sulfonates or oxide ions. Some examples of charged cationic substituents include quaternary ammonium ions (-NR3). + )and Ion (-PR3) + ), where R is independently selected from C 1-6 straight-chain alkyl, C 4-6 Branched alkyl, C 3-6 Cycloalkyl, aryl, heteroaryl, and arylalkyl or heteroarylalkyl groups. Other charged cationic substituents include protonated primary, secondary, and tertiary amines, as well as guanidine. or mitochondrial or pyridine Or other protonated, alkylated, or oxygen-containing nitrogen heterocycles. In some embodiments, the charged substituent is -N(CH3)3. + .

[0121] As used herein, the phrase "nonionic oligomeric or polymeric solubilizing group" refers to soluble polymers such as polyethylene glycol, polypropylene glycol, polyethylene oxide and propylene oxide copolymers, carbohydrates, dextran, polyacrylamide, peptides, etc. Solubilizing groups can be linked in any desired pattern. Linkage points can be, for example, carbon-carbon, carbon-oxygen, or nitrogen-carbon bonds. Linking groups can be, for example, ester groups, carbonate groups, urea groups, alcohol groups, ether groups, thioether groups, amino, alkylene, alkynyl, azide groups, tetrazine, amide groups, carbonyl, or phosphate ester groups.

[0122] Some examples of solubilizing groups include polyethylene glycol, such as -(CH2CH2O). a -H, -OC(=O)O(CH2CH2O) a H、-OC(=O)O(CH2CH2O) a CH3、-O(CH2CH2O) a CH3 and -S(CH2CH2O)2CH3, where "a" is an integer between about 2 and about 25. In some embodiments, "a" is 4 to 12 or 5 to 10. In other embodiments, "a" is 6, 7, or 8. Other examples of solubilizing groups include dextran, such as -OC(=O)O (dextran).

[0123] The absolute molecular weight of the solubilized portion can be from about 500 amu to about 100,000 amu, for example, from about 1,000 amu to about 50,000 amu or from about 1,500 to about 25,000 amu.

[0124] Other examples of solubilizing groups include: -(CH2) c -(OCH2CH2) d -OR a Where "c" is 0 to 6, "d" is 1 to 200, and R a Is it H or C? 1-6 Alkyl group. In some embodiments, "c" is 1 to 4, "d" is 1 to 10, and R a It is H. In some implementations, "d" is 6 or 7.

[0125] See WO 2008 / 017074, U.S. Serial No. 12 / 376,243 (filed February 3, 2009) and U.S. Serial No. 12 / 376,225 (filed February 3, 2009), each incorporated herein by reference in its entirety, for further description of suitable nonionic oligomeric or polymeric solubilizing groups and methods for incorporating them into dyes.

[0126] It should be further understood that, for clarity, certain features of the invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, for brevity, multiple features of the invention described in the context of a single embodiment may also be provided separately or in any suitable sub-combination.

[0127] The compounds of this invention may also contain all isotopes of the atoms appearing in the intermediates or the final compound. Isotopes include atoms that have the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[0128] Unless otherwise stated, chemical substances referred to in this document by name, chemical formula or structure are meant to include all their stereoisomers, geometric isomers, tautomers, resonance structures and isotopes.

[0129] The chemical substances described herein may be charged or contain substituents with a formal charge. When such a chemical substance is indicated as charged, it should be understood that, unless otherwise stated, the charge generally counters an ion with a suitable counter charge. For example, a chemical substance or functional group with a -1 charge should be understood as countering an ion with a +1 charge. Suitable counter ions with a +1 charge include Na+, K+, tetraalkylammonium ions, etc. Conversely, a chemical substance or functional group with a +1 charge should be understood as countering an ion with a -1 charge. Suitable counter ions with a -1 charge include F-, Cl-, Br-, I-, sulfate, phosphate, perchlorate, acetate, trifluoroacetate, maleate, fumarate, methanesulfonate, lactate, pyruvate, fructose, gluconate, etc.

[0130] zwitterionic metal chelators that coordinate with metal isotopes

[0131] In some aspects, this disclosure relates to zwitterionic metal chelators that coordinate with or are labeled with a metal or metal isotope. In some embodiments, zwitterionic metal chelators that coordinate with or are labeled with a metal or metal isotope can be used in medical, agricultural, or chemical process applications.

[0132] Some exemplary medical applications include applications for detection, imaging, or treatment in or on a subject or in a biological sample. In some embodiments, this disclosure also provides treatment of benign and malignant tumors and tumor cells using zwitterionic metal chelators labeled with radioactive metal isotopes, whereby the radioactive metal isotope emits ionizing radiation in the form of cell death that causes uptake of analogs labeled with that radioactive metal isotope. Metal chelators labeled with certain non-radioactive metal isotopes (e.g., Zr or Gd) can be used for neutron capture therapy.

[0133] The various zwitterionic metal chelating agents of the present invention, particularly those suitable for use in the imaging methods provided by the present invention, comprise one or more metals or radioactive isotopes capable of emitting one or more forms of radiation or other contrasts (e.g., relaxation of water), and are suitable for detection by any standard radiological method (e.g., PET, SPECT, gamma camera, MRI, etc.).

[0134] For the disclosed methods of detecting / imaging benign or malignant tissue, any known metal isotope emitting radiation in a form readily detectable by conventional imaging techniques can be incorporated into the target backbone. Some non-limiting examples of “conventional imaging techniques” include gamma-ray detection, PET scans, SPECT scans, and MRT scans. Some non-limiting examples of metals that can be complexed with the chelating agents of this invention include Gd, Mn, Cu, Co, Y, In, Ga, Zr, Tc, Eu, Tb, Ac, Lu, and other lanthanides or actinides. In some embodiments, the metal may be a radioactive metal isotope. Some non-limiting examples of radioactive metal isotopes that may be used include Ga-66, Ga-67, Ga-68, Cu-64, Cu-67, Y-86, Co-55, Zr-89, Sr-83, Mn-52, As-72, Sc-44, Gd-153, Co-57, In-111, Ac-225, or Tc-99m.

[0135] For the disclosed methods of therapeutic treatment of malignant tumors, any known radioactive metal isotope that emits ionizing radiation in the form of causing cell death by ingesting a radiolabeled analog can be incorporated into the zwitterionic metal chelating agent of the present invention by chelation. Non-radioactive metals capable of capturing neutrons and releasing cytotoxic radiation (neutron capture therapy) can also be incorporated in this way. In some embodiments, the radioactive metal isotope emits ionizing radiation in a form that minimizes damage to the extracellular tissue of cells that have ingested the labeled analog. In some embodiments, the present invention provides compounds comprising one or more radioactive isotopes suitable for use in radiotherapy. In some embodiments, the zwitterionic metal chelating agent of the present invention comprises at least one radioactive isotope selected from the following: technetium, rhenium, gallium, indium, copper, yttrium, actinium, bismuth, samarium, dysprosium, holmium, or lutetium, including radioactive isotopes selected from the following: Tc-99m, Tc-94m, Re-186, Re-188, Ga-68, Cu-64, Cu-67, Y-90, Y-86, Ac-225, Bi-213, In-111, Sm-153, Ho-166, Lu-177, Sc-43, Sc-44, Sc-47, Tb-149, Tb-152, Tb-155, Tb-161, and Dy-166. In other embodiments, some non-limiting examples of the metal used for neutron capture therapy include Zr-88 or Gd-157.

[0136] For the disclosed method, there are no particular limitations on the oxidation state of the metal coordinated with the chelating agent. Generally, the oxidation state can be adjusted based on the specific zwitterionic metal chelating agent used and the specific medical application. In some embodiments, the metal coordinated with the chelating agent has an oxidation state of +1 to +5.

[0137] Various zwitterionic metal chelators of the present invention can produce a target or signal to background radiation intensity ratio of at least 2:1, or more preferably, a target to background radiation intensity ratio of about 5:1, about 10:1 or about 15:1.

[0138] Furthermore, the zwitterionic metal chelating agents of the present invention are rapidly eliminated from body tissues without significant nonspecific uptake by off-target tissues and organs, thus preventing long-term exposure to radiation from radiolabeled compounds or the toxic effects of non-radioactive metals applied to patients. Typically, the zwitterionic metal chelating agents of the present invention are cleared from the body in less than about 24 hours. More preferably, the compounds of the present invention are cleared from the body in less than about 16 hours, 12 hours, 8 hours, 6 hours, 4 hours, 2 hours, 90 minutes, or 60 minutes. Typically, preferred compounds are cleared in about 60 minutes to about 120 minutes.

[0139] In some embodiments, zwitterionic metal chelates containing imaging agents or therapeutic agents are cleared from the subject's tumor, tissue, or organ. In some embodiments, zwitterionic metal chelates containing imaging agents are cleared from the subject's kidney faster than from the subject's tumor.

[0140] In some embodiments, the zwitterionic metal chelator is stable in vivo, such that substantially all (e.g., more than about 50%, 60%, 70%, 80%, or more preferably 90%) of the injected compound is not metabolized by the body before excretion. In other embodiments, the zwitterionic metal chelator is stable in vivo.

[0141] DOTA-based zwitterionic metal chelating agents

[0142] In one aspect, the present invention provides a zwitterionic metal chelating agent based on 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (also known as DOTA). Such a zwitterionic metal chelating agent comprises the following: Wherein ZWI represents a zwitterionic group; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group. In some embodiments, ZWI represents an ammonium sulfobetaine group.

[0143] In such an implementation, the DOTA-based zwitterionic metal chelate comprises a stereocenter, either of which may have an R or S configuration. The DOTA-based zwitterionic metal chelate may be a single stereoisomer or a mixture of stereoisomers. The DOTA-based zwitterionic metal chelate comprises 1, 2, 3, or 4 such... Figure 3The zwitterionic group ZWI and 1, 2, or 3 reactive groups X for conjugation with a target carrier or other molecule or material are defined herein. The reactive group can be a carboxylic acid, an activated carboxylic acid derivative, such as an NHS ester, sulfonated NHS ester, PFP ester, HOBt ester, HOAt ester, TFP ester, an anhydride, an acyl azide, or an acyl halide. The reactive group X can also be an amine, azide, alkyne, alkene, ketone, aldehyde, alcohol, phenol, maleimide, thiol, phosphine, or tetrazine. The zwitterionic group ZWI and the reactive group X are separated from the chelating agent core structure by suitable spacer portions W and Y, said spacer portions W and Y comprising alkyl, aryl, or heteroaryl groups. In some specific embodiments, the DOTA-based zwitterionic metal chelating agent comprises 1, 2, 3, or 4 zwitterionic groups and 4 carboxylic acid groups for conjugation with a metal or metal isotope. In other embodiments, the DOTA-based zwitterionic metal chelator comprises one, two, three, or four zwitterionic groups, four carboxylate groups for complexation with a metal or metal isotope, and one or more targeting supports. These targeting supports can be bound to the chelator at any suitable structural position (e.g., reactive group X), as understood by those skilled in the art in synthesizing such compounds.

[0144] DOTA-based zwitterionic metal chelators can be synthesized using the scheme described in Scheme 1.

[0145] Option 1

[0146]

[0147] Alternatively, the N-oxide functional group can be synthesized by nucleophilically substituting a suitable leaving group (e.g., a halide or sulfonate ion) instead of the group R in the above schemes. The nucleophile in these transformations is an N,N-dialkylated hydroxylamine, which is protected at the hydroxyl group.

[0148] In one specific implementation, the DOTA-based zwitterionic metal chelator can be combined with Zr, Cu, Ga, In, Y, Gd, Lu, Ac, Tb or other metals.

[0149] In other embodiments, one or more zwitterionic groups of the DOTA-based zwitterionic metal chelator can be replaced by a targeting carrier such as cRGD, dPSMA-617, KUE, small molecules targeting FAP, octreotide, bufotoxin, or their corresponding homodimers or heterodimers, provided that the DOTA-based zwitterionic metal chelator retains the zwitterionic group. In some embodiments, the targeting ligand comprises one or more of the following: having The LyP-1 peptide, which contains the sequence and binds to P32, is used for the diagnosis / treatment of melanoma; it has... The K237 peptide, which contains the sequence and binds to VEGFR-2, is used for the diagnosis / treatment of breast tumors; it has The IL4RPep-1 peptide, which contains the sequence of IL4R and binds to IL4R, is used for the diagnosis / treatment of lung cancer, breast cancer, and colon cancer; it has... The sequence of the mUNO peptide, which binds to CD206, is used for the diagnosis / treatment of breast cancer; the folic acid receptor, for the diagnosis / treatment of ovarian and lung cancer; and the dodecapeptide GE11, which binds to the epidermal growth factor receptor (EGFR or ErbB1), for the diagnosis / treatment of epithelial-derived tumors. Alternatively, the targeting vector can be covalently linked to the reactive linker group of the chelating agent compound of the present invention via standard coupling operations. For example, the carboxyl or activated carboxyl group of the reactive linker group can react with a nucleophilic functional group (e.g., an amine or alcohol derivative) on the targeting vector to form an amide or ester bond. Further details of the conjugation can be found in WO 2008 / 017074 and Frangioni et al. Molecular Imaging, Vol. 1(4), 354-364 (2002), each of which is incorporated herein by reference in its entirety.

[0150] It will be apparent to those skilled in the art that if the target carrier replaces the zwitterionic group, the zwitterionic group can be restored by adding it to the junction between the zwitterionic metal chelator and the target carrier. The resulting conjugate structure is... Figure 5 As shown in the image. Zwitterions (such as...) Figure 3 The target carrier (TV) can be separated from the chelating agent core structure by a suitable spacer portion Y, said spacer portion Y comprising an alkyl, aryl, or heteroaryl group. The target carrier (TV) can be separated from the chelating agent core structure by a suitable spacer portion W, said spacer portion W comprising an alkyl, aryl, heteroaryl, ether, ester, amide, imine, or oxime group. The spacer portion Y may also comprise one or more ether or amide bonds or a combination thereof, and may comprise zwitterionic groups added to the side chains of the spacer portion. In some embodiments, each of W and Y may be independently absent.

[0151] In some embodiments, the reagent also contains a PEG moiety to alter circulation time in the blood. Such a moiety can bind to the conjugate at any suitable structural location, as understood by those skilled in the art to synthesize such compounds.

[0152] In some embodiments, the DOTA-based zwitterionic metal chelate conjugate with the targeting carrier has the following formula, wherein KUE, dPSMA-617, cRGD, FAPI, octreotide, bufotalin, or other substances are used as the targeting carrier (tv):

[0153] In some implementations, the targeting ligand comprises one or more of the following: having The LyP-1 peptide, which contains the sequence and binds to P32, is used for the diagnosis / treatment of melanoma; it has... The K237 peptide, which contains the sequence and binds to VEGFR-2, is used for the diagnosis / treatment of breast tumors; it has The IL4RPep-1 peptide, which contains the sequence of IL4R and binds to IL4R, is used for the diagnosis / treatment of lung cancer, breast cancer, and colon cancer; it has... The sequence of mUNO peptide, which binds to CD206, is used for the diagnosis / treatment of breast tumors; the folic acid receptor, used for the diagnosis / treatment of ovarian and lung cancer; and the dodecapeptide GE11, which binds to the epidermal growth factor receptor (EGFR or ErbB1), is used for the diagnosis / treatment of epithelial tumors.

[0154] Such DOTA-based zwitterionic conjugates can be synthesized using the scheme described in Scheme 2 (in Figure 5 (As shown in the diagram). Alternatively, the N-oxide functional group can be synthesized by nucleophilically substituting a suitable leaving group (e.g., a halide or sulfonate group) instead of the group R in this scheme. The nucleophile in these transformations is an N,N-dialkylated hydroxylamine, which is protected at the hydroxyl group.

[0155] In some implementations, the DOTA-based zwitterionic metal chelator is not ZWI3-DOTA-Ahx-cRGD.

[0156] In some implementations, the DOTA-based zwitterionic metal chelator is not: .

[0157] In some implementations, the DOTA-based zwitterionic metal chelator is not:

[0158] PyC3A-based zwitterionic metal chelators

[0159] In one aspect, the present invention provides a zwitterionic metal chelating agent based on N-pyridylmethyl-N,N',N'-trans-1,2-cyclohexenediamine triacetate / ester (also known as PyC3A). Such a zwitterionic metal chelating agent comprises the following:

[0160] In such an implementation, the PyC3A-based zwitterionic metal chelating agent comprises 1, 2, 3, or 4 such... Figure 3The zwitterionic group ZWI and one, two, or three reactive groups X for conjugation with a target carrier or other molecule or material are defined herein. The reactive group can be a carboxylic acid, an activated carboxylic acid derivative such as an NHS ester, a sulfonated NHS ester, a PFP ester, a HOBt ester, a HOAt ester, a TFP ester, an anhydride, an acyl azide, or an acyl halide. The reactive group X can also be an amine, an azide, an alkyne, an alkene, a ketone, an aldehyde, an alcohol, a phenol, a maleimide, a thiol, a phosphine, or a tetrazine. The zwitterionic group ZWI and the reactive group X are separated from the chelating agent core structure by suitable spacer portions W and Y, said spacer portions W and Y comprising alkyl, aryl, or heteroaryl groups. In some embodiments, each of W and Y may be independently absent. In some embodiments, ZWI represents an ammonium sulfobetaine group.

[0161] PyC3A-based zwitterionic metal chelators can be synthesized using the scheme described in Scheme 3.

[0162] Option 3

[0163]

[0164] Alternatively, the N-oxide functional group can be synthesized by nucleophilically substituting a suitable leaving group (e.g., a halide or sulfonate group) instead of the group R in the above schemes. The nucleophile in these transformations is an N,N-dialkylated hydroxylamine, which is protected at the hydroxyl group.

[0165] In one specific implementation, the PyC3A-based zwitterionic metal chelator can be combined with Mn or similar metals.

[0166] In other embodiments, one or more zwitterionic groups of the PyC3A-based zwitterionic metal chelator can be replaced with a targeting carrier such as cRGD, PSMA-617, FAPI, octreotide, bufotalin, or a corresponding homodimer or heterodimer, provided that the PyC3A-based zwitterionic metal chelator retains the zwitterionic group. In some embodiments, the targeting ligand comprises one or more of the following: having The LyP-1 peptide, which contains the sequence and binds to P32, is used for the diagnosis / treatment of melanoma; it has... The K237 peptide, which contains the sequence and binds to VEGFR-2, is used for the diagnosis / treatment of breast tumors; it has The IL4RPep-1 peptide, which contains the sequence of IL4R and binds to IL4R, is used for the diagnosis / treatment of lung cancer, breast cancer, and colon cancer; it has... The sequence of the mUNO peptide, which binds to CD206, is used for the diagnosis / treatment of breast cancer; the folic acid receptor, for the diagnosis / treatment of ovarian and lung cancer; and the dodecapeptide GE11, which binds to the epidermal growth factor receptor (EGFR or ErbB1), for the diagnosis / treatment of epithelial-derived tumors. Alternatively, the targeting vector can be covalently linked to the reactive linker group of the chelating agent compound of the present invention via standard coupling operations. For example, the carboxyl group or activated carboxyl group of the reactive linker group can react with a nucleophilic functional group (e.g., an amine or alcohol derivative) on the targeting vector to form an amide or ester bond. Further details of the conjugation can be found in WO 2008 / 017074 and Frangaoni et al. Molecular Imaging, Vol. 1(4), 354-364 (2002), each of which is incorporated herein by reference in its entirety.

[0167] It will be apparent to those skilled in the art that if the target carrier replaces the zwitterionic group, the zwitterionic group can be restored by adding it to the junction between the zwitterionic metal chelator and the target carrier. The resulting conjugate structure is shown below:

[0168] Zwitterion ZWI (e.g.) Figure 3 The target carrier (TV) can be separated from the chelating agent core structure by a suitable spacer portion Y, said spacer portion Y comprising alkyl, aryl, or heteroaryl groups. The target carrier (TV) can be separated from the chelating agent core structure by a suitable spacer portion W, said spacer portion W comprising alkyl, aryl, heteroaryl, ether, ester, amide, imine, and oxime groups. The spacer portion Y may also comprise one or more ether or amide bonds or a combination thereof, and may include zwitterionic groups on the side chains added to the spacer portion.

[0169] In some embodiments, the reagent also contains a PEG moiety to alter circulation time in the blood. Such a moiety can bind to the conjugate at any suitable structural location, as understood by those skilled in the art to synthesize such compounds.

[0170] Macropa-based zwitterionic metal chelators

[0171] In one aspect, the present invention provides a macropa-based zwitterionic metal chelating agent. Such a zwitterionic metal chelating agent includes the following:

[0172] In such an implementation, the macropa-based zwitterionic metal chelator comprises one or two such... Figure 3The zwitterionic group ZWI and one or two reactive groups X for conjugation with a target carrier or other molecule or material are defined herein. The reactive group can be a carboxylic acid, an activated carboxylic acid derivative, such as an NHS ester, a sulfonated NHS ester, a PFP ester, a HOBt ester, a HOAt ester, a TFP ester, an anhydride, an acyl azide, or an acyl halide. The reactive group X can also be an amine, an azide, an alkyne, an alkene, a ketone, an aldehyde, an alcohol, a phenol, a maleimide, a thiol, a phosphine, or a tetrazine. The zwitterionic group ZWI and the reactive group X are separated from the chelating agent core structure by suitable spacer portions W and Y, said spacer portions W and Y comprising alkyl, aryl, or heteroaryl groups. In some embodiments, each of W and Y may be independently absent.

[0173] In some specific implementations, macropa-based zwitterionic metal chelators have the following formula:

[0174] ZWI represents a zwitterionic group. In some embodiments, ZWI represents an ammonium sulfobetaine group.

[0175] Macropa-based zwitterionic metal chelators can be synthesized using the scheme described in Scheme 4.

[0176] Option 4

[0177]

[0178] Alternatively, the N-oxide functional group can be synthesized by nucleophilically substituting a suitable leaving group (e.g., a halide or sulfonate group) instead of the group R in the above schemes. The nucleophile in these transformations is an N,N-dialkylated hydroxylamine, which is protected at the hydroxyl group.

[0179] In one specific implementation, a macropa-based zwitterionic metal chelator can react with Ac 3+ Bi 3+ Or similar metal cation complexes.

[0180] In other embodiments, one or more zwitterionic groups of the macropa-based zwitterionic metal chelator can be replaced by a targeting carrier such as cRGD, dPSMA-617, KUE, small molecules targeting FAP, octreotide, bufotoxin, or their corresponding homodimers or heterodimers, provided that the macropa-based zwitterionic metal chelator retains the zwitterionic group. In some embodiments, the targeting ligand comprises one or more of the following: having The LyP-1 peptide, which contains the sequence and binds to P32, is used for the diagnosis / treatment of melanoma; it has... The K237 peptide, which contains the sequence and binds to VEGFR-2, is used for the diagnosis / treatment of breast tumors; it has The IL4RPep-1 peptide, which contains the sequence of IL4R and binds to IL4R, is used for the diagnosis / treatment of lung cancer, breast cancer, and colon cancer; it has... The sequence of the mUNO peptide, which binds to CD206, is used for the diagnosis / treatment of breast cancer; the folic acid receptor, for the diagnosis / treatment of ovarian and lung cancer; and the dodecapeptide GE11, which binds to the epidermal growth factor receptor (EGFR or ErbB1), for the diagnosis / treatment of epithelial-derived tumors. Alternatively, the targeting vector can be covalently linked to the reactive linker group of the chelating agent compound of the present invention via standard coupling operations. For example, the carboxyl group or activated carboxyl group of the reactive linker group can react with a nucleophilic functional group (e.g., an amine or alcohol derivative) on the targeting vector to form an amide or ester bond. Further details of the conjugation can be found in WO 2008 / 017074 and Frangioni et al. Molecular Imaging, Vol. 1(4), 354-364 (2002), each of which is incorporated herein by reference in its entirety.

[0181] It will be apparent to those skilled in the art that if the target carrier replaces the zwitterionic group, the zwitterionic group can be restored by adding it to the junction between the zwitterionic metal chelator and the target carrier. The resulting conjugate structure is shown in Figure 7. Zwitterionic ZWI (e.g. Figure 3 The target carrier (TV) can be separated from the chelating agent core structure by a suitable spacer portion Y, said spacer portion Y comprising an alkyl, aryl, or heteroaryl group. The target carrier (TV) can be separated from the chelating agent core structure by a suitable spacer portion W, said spacer portion W comprising an alkyl, aryl, heteroaryl, ether, ester, amide, imine, or oxime group. The spacer portion Y may also comprise one or more ether or amide bonds or a combination thereof, and may comprise zwitterionic groups added to the side chains of the spacer portion. In some embodiments, each of W and Y may be independently absent.

[0182] Macropa-based zwitterionic chelates and targeting carriers (TV) conjugates include, but are not limited to:

[0183] In some embodiments, the reagent also contains a PEG moiety to alter circulation time in the blood. Such a moiety can bind to the conjugate at any suitable structural location, as understood by those skilled in the art to synthesize such compounds.

[0184] Porphyrin-based zwitterionic metal chelators

[0185] In one aspect, the present invention provides a porphyrin-based zwitterionic metal chelating agent. Such a zwitterionic metal chelating agent comprises the following:

[0186] In such an implementation, the porphyrin-based zwitterionic metal chelating agent comprises 1, 2, 3, or 4 such... Figure 3 The zwitterionic group ZWI and one or two reactive groups X for conjugation with a target carrier or other molecule or material are defined herein. The reactive group can be a carboxylic acid, an activated carboxylic acid derivative, such as an NHS ester, a sulfonated NHS ester, a PFP ester, a HOBt ester, a HOAt ester, a TFP ester, an anhydride, an acyl azide, or an acyl halide. The reactive group X can also be an amine, an azide, an alkyne, an alkene, a ketone, an aldehyde, an alcohol, a phenol, a maleimide, a thiol, a phosphine, or a tetrazine. The zwitterionic group ZWI and the reactive group X are separated from the chelating agent core structure by suitable spacer portions W and Y, said spacer portions W and Y comprising alkyl, aryl, or heteroaryl groups. In some embodiments, each of W and Y may be independently absent. In some specific embodiments, the porphyrin-based zwitterionic metal chelator comprises four zwitterionic groups. In some embodiments, ZWI represents an ammonium sulfobetaine group.

[0187] In some embodiments, the chelating agent comprises a reactive linking group, typically an activated carboxylic acid derivative, such as an NHS ester, sulfonyl-NHS ester, PFP ester, HOBt ester, HOAt ester, TFP ester, an anhydride, an acyl azide, or an acyl halide. As will be understood by those skilled in the art in synthesizing such compounds, such a reactive linking group can be attached to or substituted onto the chelating agent at any suitable structural position.

[0188] In some specific implementations, the porphyrin-based zwitterionic metal chelating agent has the following formula:

[0189] The zwitterion is a pyridine-N-oxide (as shown above) or aromatic N-oxide derived from imidazole, pyrimidine, or similar heteroaromatic residues. X is a reactive group for conjugation with a target carrier or other molecule or material. This reactive group can be a carboxylic acid, an activated carboxylic acid derivative such as an NHS ester, a sulfonated NHS ester, a PFP ester, a HOBt ester, a HOAt ester, a TFP ester, an anhydride, an acyl azide, or an acyl halide. Reactive group X can also be an amine, an azide, an alkyne, an alkene, a ketone, an aldehyde, an alcohol, a phenol, a maleimide, a thiol, a phosphine, or a tetrazine. Reactive group X can be separated from the chelating agent core structure by a suitable spacer moiety W, which comprises an alkyl, aryl, or heteroaromatic group. In some embodiments, each of W and Y may be independently absent.

[0190] Porphyrin-based zwitterionic metal chelators can be synthesized using the scheme described in Scheme 5.

[0191] Option 5

[0192]

[0193] Alternatively, the N-oxide functional group can be synthesized by nucleophilically substituting a suitable leaving group (e.g., a halide or sulfonate group) instead of the group R in the above schemes. The nucleophile in these transformations is an N,N-dialkylated hydroxylamine, which is protected at the hydroxyl group.

[0194] In one specific implementation, a porphyrin-based zwitterionic metal chelator can react with Mn 2+ Mn 3+ Fe 2+ Fe 3 + Gd 3+ Ac 3+ Bi 3+ Or similar metal cation complexes.

[0195] In one specific implementation, the porphyrin-based zwitterionic metal chelator has the following formula:

[0196] In other embodiments, one or more zwitterionic groups of the porphyrin-based zwitterionic metal chelator may be replaced by a targeting carrier such as cRGD, dPSMA-617, KUE, small molecules targeting FAP, octreotide, bufotoxin, or their corresponding homodimers or heterodimers, provided that the porphyrin-based zwitterionic metal chelator retains the zwitterionic group. In some embodiments, the targeting ligand comprises one or more of the following: having The LyP-1 peptide, which contains the sequence and binds to P32, is used for the diagnosis / treatment of melanoma; it has... The K237 peptide, which contains the sequence and binds to VEGFR-2, is used for the diagnosis / treatment of breast tumors; it has The IL4RPep-1 peptide, which contains the sequence of IL4R and binds to IL4R, is used for the diagnosis / treatment of lung cancer, breast cancer, and colon cancer; it has... The sequence of the mUNO peptide, which binds to CD206, is used for the diagnosis / treatment of breast cancer; the folic acid receptor, for the diagnosis / treatment of ovarian and lung cancer; and the dodecapeptide GE11, which binds to the epidermal growth factor receptor (EGFR or ErbB1), for the diagnosis / treatment of epithelial-derived tumors. Alternatively, the targeting vector can be covalently linked to the reactive linker group of the chelating agent compound of the present invention via standard coupling operations. For example, the carboxyl group or activated carboxyl group of the reactive linker group can react with a nucleophilic functional group (e.g., an amine or alcohol derivative) on the targeting vector to form an amide or ester bond. Further details of the conjugation can be found in WO 2008 / 017074 and Frangioni et al. Molecular Imaging, Vol. 1(4), 354-364 (2002), each of which is incorporated herein by reference in its entirety.

[0197] It will be apparent to those skilled in the art that if the target carrier replaces the zwitterionic group, the zwitterionic group can be restored by adding it to the junction between the zwitterionic metal chelator and the target carrier. The resulting conjugate structure is shown in Figure 8. Zwitterionic ZWI (e.g. Figure 3 The target carrier (TV) can be separated from the chelating agent core structure by a suitable spacer portion Y, said spacer portion Y comprising an alkyl, aryl, or heteroaryl group. The target carrier (TV) can be separated from the chelating agent core structure by a suitable spacer portion W, said spacer portion W comprising an alkyl, aryl, heteroaryl, ether, ester, amide, imine, or oxime group. The spacer portion Y may also comprise one or more ether or amide bonds or a combination thereof, and may comprise zwitterionic groups added to the side chains of the spacer portion. In some embodiments, each of W and Y may be independently absent.

[0198] Conjugates of porphyrin-based zwitterionic chelators and targeting carriers (TV) include, but are not limited to:

[0199] In some embodiments, the porphyrin-based zwitterionic metal chelating agent has the following formula:

[0200] The zwitterions are derived from pyridine-N-oxides (as shown above) or aromatic N-oxides of imidazole, pyrimidine, or similar heteroaromatic residues.

[0201] In some embodiments, the reagent also contains a PEG moiety to alter circulation time in the blood. Such a moiety can bind to the conjugate at any suitable structural location, as understood by those skilled in the art to synthesize such compounds.

[0202] NOTA-based zwitterionic metal chelating agents

[0203] In one aspect, the present invention provides a NOTA-based zwitterionic metal chelating agent. Such a zwitterionic metal chelating agent includes the following:

[0204] In such embodiments, the NOTA-based zwitterionic metal chelating agent comprises one, two, or three zwitterionic groups. In some specific embodiments, the NOTA-based zwitterionic metal chelating agent comprises two zwitterionic groups, such as... Figure 3 The zwitterionic group ZWI and one or two reactive groups X for conjugation with a target carrier or other molecule or material are defined herein. The reactive group can be a carboxylic acid, an activated carboxylic acid derivative, such as an NHS ester, a sulfonated NHS ester, a PFP ester, a HOBt ester, a HOAt ester, a TFP ester, an anhydride, an acyl azide, or an acyl halide. The reactive group X can also be an amine, an azide, an alkyne, an alkene, a ketone, an aldehyde, an alcohol, a phenol, a maleimide, a thiol, a phosphine, or a tetrazine. The zwitterionic group ZWI and the reactive group X are separated from the chelating agent core structure by suitable spacer portions W and Y, said spacer portions W and Y comprising alkyl, aryl, or heteroaryl groups. In some embodiments, each of W and Y may be independently absent.

[0205] In some specific implementations, the NOTA-based zwitterionic metal chelating agent has the following formula:

[0206] Such NOTA-based zwitterionic metal chelators can be synthesized using the scheme described in Scheme 6.

[0207] Option 6

[0208]

[0209] Alternatively, the N-oxide functional group can be synthesized by nucleophilically substituting a suitable leaving group (e.g., a halide or sulfonate group) instead of the group R in the above schemes. The nucleophile in these transformations is an N,N-dialkylated hydroxylamine, which is protected at the hydroxyl group.

[0210] In one specific implementation, a NOTA-based zwitterionic metal chelator can react with Ga... 3+ Cu 2+ Gd 3+ Ac 3 + Bi 3+ Or similar metal cation complexes.

[0211] In other embodiments, one or more zwitterionic groups of the NOTA-based zwitterionic metal chelator may be replaced by a targeting carrier such as cRGD, dPSMA-617, KUE, small molecules targeting FAP, octreotide, bufotoxin, or their corresponding homodimers and heterodimers, provided that the NOTA-based zwitterionic metal chelator retains the zwitterionic group. In some embodiments, the targeting ligand comprises one or more of the following: having The LyP-1 peptide, which contains the sequence and binds to P32, is used for the diagnosis / treatment of melanoma; it has... The K237 peptide, which contains the sequence and binds to VEGFR-2, is used for the diagnosis / treatment of breast tumors; it has The IL4RPep-1 peptide, which contains the sequence of IL4R and binds to IL4R, is used for the diagnosis / treatment of lung cancer, breast cancer, and colon cancer; it has... The sequence of the mUNO peptide, which binds to CD206, is used for the diagnosis / treatment of breast cancer; the folic acid receptor, for the diagnosis / treatment of ovarian and lung cancer; and the dodecapeptide GE11, which binds to the epidermal growth factor receptor (EGFR or ErbB1), for the diagnosis / treatment of epithelial-derived tumors. Alternatively, the targeting carrier can be covalently linked to the reactive linker group of the chelating agent compound of the present invention via standard coupling operations. For example, the carboxyl group or activated carboxyl group of the reactive linker group can react with a nucleophilic functional group (e.g., an amine or alkoxy derivative) on the targeting carrier to form an amide or ester bond. Further details of the conjugation can be found in WO 2008 / 017074 and Frangioni et al. Molecular Imaging, Vol. 1(4), 354-364 (2002), each of which is incorporated herein by reference in its entirety.

[0212] It will be apparent to those skilled in the art that if the target carrier replaces the zwitterionic group, the zwitterionic group can be restored by adding it to the junction between the zwitterionic metal chelator and the target carrier. The resulting conjugate structure is shown in Figure 9. Zwitterionic ZWI (e.g. Figure 3 The target carrier (TV) can be separated from the chelating agent core structure by a suitable spacer portion Y, said spacer portion Y comprising an alkyl, aryl, or heteroaryl group. The target carrier (TV) can be separated from the chelating agent core structure by a suitable spacer portion W, said spacer portion W comprising an alkyl, aryl, heteroaryl, ether, ester, amide, imine, or oxime group. The spacer portion Y may also comprise one or more ether or amide bonds or a combination thereof, and may comprise zwitterionic groups added to the side chains of the spacer portion. In some embodiments, each of W and Y may be independently absent.

[0213] Conjugates of NOTA-based zwitterionic chelators and targeting carriers (TV) include, but are not limited to:

[0214] In some embodiments, the reagent also contains a PEG moiety to alter circulation time in the blood. Such a moiety can bind to the conjugate at any suitable structural location, as understood by those skilled in the art to synthesize such compounds.

[0215] zwitterionic metal chelators based on deferroamine

[0216] In one aspect, the present invention provides zwitterionic metal chelators based on deferoxamine. Such zwitterionic metal chelators include the following:

[0217] In such an implementation, the deferoxamine-based zwitterionic metal chelator with four isohydroxamate groups is derived from DFO. Furthermore, deferoxamine-based zwitterionic metal chelators with three isohydroxamate groups are derived from DFO. These deferoxamine-based zwitterionic metal chelators contain one, two, three, or four such groups. Figure 3 The zwitterionic group ZWI and one or two reactive groups X for conjugation with a target carrier or other molecule or material are defined herein. The reactive group can be a carboxylic acid, an activated carboxylic acid derivative, such as an NHS ester, a sulfonated NHS ester, a PFP ester, a HOBt ester, a HOAt ester, a TFP ester, an anhydride, an acyl azide, or an acyl halide. The reactive group X can also be an amine, an azide, an alkyne, an alkene, a ketone, an aldehyde, an alcohol, a phenol, a maleimide, a thiol, a phosphine, or a tetrazine. The zwitterionic group ZWI and the reactive group X can be separated from the chelating agent core structure by suitable spacer portions W and Y, said spacer portions W and Y comprising alkyl, aryl, or heteroaryl groups. In some embodiments, each of W and Y may be independently absent. In other embodiments, WX may represent hydrogen or an alkyl group.

[0218] In some embodiments, the chelating agent comprises a reactive linking group, typically an activated carboxylic acid derivative, such as an NHS ester, sulfonyl-NHS ester, PFP ester, HOBt ester, HOAt ester, TFP ester, an anhydride, an acyl azide, or an acyl halide. As will be understood by those skilled in the art in synthesizing such compounds, such a reactive linking group can be attached to or substituted onto the chelating agent at any suitable structural position.

[0219] Such zwitterionic metal chelators based on deferoxamine can be synthesized using the scheme described in Scheme 7. Figure 6Alternatively, the N-oxide functional group can be synthesized by nucleophilically substituting a suitable leaving group (e.g., a halide or sulfonate group) instead of the group R in this scheme. The nucleophile in these transformations is an N,N-dialkylated hydroxylamine, which is protected at the hydroxyl group.

[0220] In one specific implementation, the zwitterionic metal chelating agent based on deferoxamine can react with Zr. 4+ Fe 3+ Mn 2+ Mn 3+ Or similar metal cation complexes.

[0221] In other embodiments, the deferoxamine-based zwitterionic metal chelator can be conjugated with targeting carriers such as cRGD, dPSMA-617, KUE, small molecules targeting FAP, octreotide, bufotoxin, or their corresponding homodimers and heterodimers, provided that the deferoxamine-based zwitterionic metal chelator retains the zwitterionic ion. In some embodiments, the targeting ligand comprises one or more of the following: having The LyP-1 peptide, which contains the sequence and binds to P32, is used for the diagnosis / treatment of melanoma; it has... The K237 peptide, which contains the sequence and binds to VEGFR-2, is used for the diagnosis / treatment of breast tumors; it has The IL4RPep-1 peptide, which contains the sequence of IL4R and binds to IL4R, is used for the diagnosis / treatment of lung cancer, breast cancer, and colon cancer; it has... The sequence of the mUNO peptide, which binds to CD206, is used for the diagnosis / treatment of breast cancer; the folic acid receptor, for the diagnosis / treatment of ovarian and lung cancer; and the dodecapeptide GE11, which binds to the epidermal growth factor receptor (EGFR or ErbB1), for the diagnosis / treatment of epithelial-derived tumors. The targeting vector can be covalently linked to the reactive linker group of the chelating agent compound of the present invention via standard coupling operations. For example, the carboxyl group or activated carboxyl group of the reactive linker group can react with a nucleophilic functional group (e.g., an amine or alcohol derivative) on the targeting vector to form an amide or ester bond. Further details of the conjugation can be found in WO 2008 / 017074 and Frangioni et al. Molecular Imaging, Vol. 1(4), 354-364 (2002), each of which is incorporated herein by reference in its entirety. Alternatively, other reactive groups X can be used for the conjugation of the targeting vector. For example, amine groups can react with electrophiles (e.g., carboxylic acids, activated derivatives thereof, or isocyanates / esters) to form amide or urea bonds. Amines can also be converted by other chemical transformations (e.g., nucleophilic substitution or reductive amination) to provide physiologically stable bonds with the target carrier. One or two reactive groups at any position of a zwitterionic chelator based on deferoxamine can be used for the conjugation of one or more target carriers. Two examples of the resulting conjugates are shown in Figure 10. Zwitterionic ZWIs (such as...) Figure 3 The target carrier (TV) can be separated from the chelating agent core structure by a suitable spacer portion Y, said spacer portion Y comprising an alkyl, aryl, or heteroaryl group. The target carrier (TV) can be separated from the chelating agent core structure by a suitable spacer portion W, said spacer portion W comprising an alkyl, aryl, heteroaryl, ether, ester, amide, imine, or oxime group. The spacer portion Y may also comprise one or more ether or amide bonds or a combination thereof, and may comprise zwitterionic groups added to the side chains of the spacer portion. In some embodiments, each of W and Y may be independently absent.

[0222] Exemplary conjugates of zwitterionic chelators based on deferoxamine and targeting carriers (TV) include, but are not limited to:

[0223] In some embodiments, the reagent also contains a PEG moiety to alter circulation time in the blood. Such a moiety can bind to the conjugate at any suitable structural location, as understood by those skilled in the art to synthesize such compounds.

[0224] DOTAM-based zwitterionic metal chelators

[0225] In one aspect, the present invention provides a zwitterionic metal chelating agent based on 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetamide (also known as DOTAM). DOTAM is a derivative of DOTA, wherein the -COOH group is replaced by a -CONR2 group. Such zwitterionic metal chelating agents include the following:

[0226] Wherein ZWI represents an amphoteric group; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group. In some embodiments, ZWI represents an ammonium sulfobetaine group. In other embodiments, ZWI represents an N-oxide group. The substituent R is hydrogen or an alkyl group or a combination of both.

[0227] In such an implementation, the DOTAM-based zwitterionic metal chelate comprises a stereocenter, either of which may have an R or S configuration. The DOTAM-based zwitterionic metal chelate may be a single stereoisomer or a mixture of stereoisomers. The DOTAM-based zwitterionic metal chelate comprises 1, 2, 3, or 4 such... Figure 3 The zwitterionic group ZWI and 1, 2, or 3 reactive groups X for conjugation with a target carrier or other molecule or material are defined herein. The reactive group can be a carboxylic acid, an activated carboxylic acid derivative, such as an NHS ester, a sulfonated NHS ester, a PFP ester, a HOBt ester, a HOAt ester, a TFP ester, an anhydride, an acyl azide, or an acyl halide. The reactive group X can also be an amine, an azide, an alkyne, an alkene, a ketone, an aldehyde, an alcohol, a phenol, a maleimide, a thiol, a phosphine, or a tetrazine. The zwitterionic group ZWI and the reactive group X are separated from the chelating agent core structure by suitable spacer portions W and Y, which contain alkyl, aryl, or heteroaryl groups. In some specific embodiments, the DOTAM-based zwitterionic metal chelating agent comprises 1, 2, 3, or 4 zwitterionic groups and 4 carboxylate groups for conjugation with a metal or metal isotope. In other embodiments, the DOTAM-based zwitterionic metal chelator comprises one, two, three, or four zwitterionic groups, four carboxylate groups for complexation with a metal or metal isotope, and one or more targeting supports. These targeting supports can be bound to the chelator at any suitable structural position (e.g., reactive group X), as understood by those skilled in the art in synthesizing such compounds.

[0228] DOTAM-based zwitterionic metal chelators can be synthesized using the scheme described in Scheme 8.

[0229] Option 8

[0230]

[0231] Alternatively, the N-oxide functional group can be synthesized by nucleophilically substituting a suitable leaving group (e.g., a halide or sulfonate group) instead of the group R in the above schemes. The nucleophile in these transformations is an N,N-dialkylated hydroxylamine, which is protected at the hydroxyl group.

[0232] In one specific implementation, the DOTAM-based zwitterionic metal chelator can be combined with Pb, Zr, Cu, Ga, In, Y, Gd, Lu, Ac, Tb, Pb, Pd or other metals.

[0233] In other embodiments, one or more zwitterionic groups of the DOTAM-based zwitterionic metal chelator may be replaced by a targeting carrier such as cRGD, dPSMA-617, KUE, small molecules targeting FAP, octreotide, bufotoxin, or their corresponding homodimers or heterodimers, provided that the DOTAM-based zwitterionic metal chelator retains the zwitterionic group. In some embodiments, the targeting ligand comprises one or more of the following: having The LyP-1 peptide, which contains the sequence and binds to P32, is used for the diagnosis / treatment of melanoma; it has... The K237 peptide, which contains the sequence and binds to VEGFR-2, is used for the diagnosis / treatment of breast tumors; it has The IL4RPep-1 peptide, which contains the sequence of IL4R and binds to IL4R, is used for the diagnosis / treatment of lung cancer, breast cancer, and colon cancer; it has... The sequence of the mUNO peptide, which binds to CD206, is used for the diagnosis / treatment of breast cancer; the folic acid receptor, for the diagnosis / treatment of ovarian and lung cancer; and the dodecapeptide GE11, which binds to the epidermal growth factor receptor (EGFR or ErbB1), for the diagnosis / treatment of epithelial-derived tumors. Alternatively, the targeting vector can be covalently linked to the reactive linker group of the chelating agent compound of the present invention via standard coupling operations. For example, the carboxyl group or activated carboxyl group of the reactive linker group can react with a nucleophilic functional group (e.g., an amine or alcohol derivative) on the targeting vector to form an amide or ester bond. Further details of the conjugation can be found in WO 2008 / 017074 and Frangioni et al. Molecular Imaging, Vol. 1(4), 354-364 (2002), each of which is incorporated herein by reference in its entirety.

[0234] It will be apparent to those skilled in the art that if the target carrier replaces the zwitterionic group, the zwitterionic group can be restored by adding it to the junction between the zwitterionic metal chelator and the target carrier. The resulting conjugate structure is... Figure 5As shown in the image. Zwitterions (such as...) Figure 3 The target carrier (TV) can be separated from the chelating agent core structure by a suitable spacer portion Y, said spacer portion Y comprising an alkyl, aryl, or heteroaryl group. The target carrier (TV) can be separated from the chelating agent core structure by a suitable spacer portion W, said spacer portion W comprising an alkyl, aryl, heteroaryl, ether, ester, amide, imine, or oxime group. The spacer portion Y may also comprise one or more ether or amide bonds or a combination thereof, and may comprise zwitterionic groups added to the side chains of the spacer portion. In some embodiments, each of W and Y may be independently absent.

[0235] In some embodiments, the reagent also contains a PEG moiety to alter circulation time in the blood. Such a moiety can bind to the conjugate at any suitable structural location, as understood by those skilled in the art to synthesize such compounds.

[0236] In some embodiments, the DOTAM-based zwitterionic metal chelator conjugate with the targeting carrier has the following formula, wherein KUE, dPSMA-617, cRGD, FAPI, octreotide, bufotalin, or other substances are used as the targeting carrier (tv):

[0237] In some implementations, the targeting ligand comprises one or more of the following: having The LyP-1 peptide, which contains the sequence and binds to P32, is used for the diagnosis / treatment of melanoma; it has... The K237 peptide, which contains the sequence and binds to VEGFR-2, is used for the diagnosis / treatment of breast tumors; it has The IL4RPep-1 peptide, which contains the sequence of IL4R and binds to IL4R, is used for the diagnosis / treatment of lung cancer, breast cancer, and colon cancer; it has... The sequence of mUNO peptide, which binds to CD206, is used for the diagnosis / treatment of breast tumors; the folic acid receptor, used for the diagnosis / treatment of ovarian and lung cancer; and the dodecapeptide GE11, which binds to the epidermal growth factor receptor (EGFR or ErbB1), is used for the diagnosis / treatment of epithelial tumors.

[0238] Targeted vector

[0239] In some embodiments of the metal chelating agent of the present invention, one or more zwitterionic groups of the zwitterionic metal chelating agent may be replaced by a targeting carrier, such as cRGD, PSMA binding carrier (e.g., PSMA-617 or KUE), a molecule targeting FAP (FAP inhibitor or FAPI), octreotide, bufotoxin, or their corresponding homodimers and heterodimers, provided that the zwitterionic metal chelating agent retains zwitterions.

[0240] In some embodiments of the present invention, the targeting ligand according to the present invention may be a cyclic RGD having the following structure:

[0241] In some embodiments, the FAPI targeting ligand comprises NH2-FAPI-74. Specific details regarding NH2-FAPI-74 are described in Linder et al., “Radioligands Targeting Fibroblast Activation Protein (FAP),” the entirety of which is incorporated herein by reference. Generally, NH2-FAPI-74 has the following structure: The FAPI targeting ligand comprises NH2-FAPI-74.

[0242] In some implementations, the targeting ligand comprises one or more of the following: having The LyP-1 peptide, which contains the sequence and binds to P32, is used for the diagnosis / treatment of melanoma; it has... The K237 peptide, which contains the sequence and binds to VEGFR-2, is used for the diagnosis / treatment of breast tumors; it has The IL4RPep-1 peptide, which contains the sequence of IL4R and binds to IL4R, is used for the diagnosis / treatment of lung cancer, breast cancer, and colon cancer; it has... The sequence of mUNO peptide, which binds to CD206, is used for the diagnosis / treatment of breast tumors; the folic acid receptor, used for the diagnosis / treatment of ovarian and lung cancer; and the dodecapeptide GE11, which binds to the epidermal growth factor receptor (EGFR or ErbB1), is used for the diagnosis / treatment of epithelial tumors.

[0243] In one specific aspect, the present invention provides zwitterionic metal chelators conjugated to targeting carriers for prostate-specific membrane antigen (PSMA). For example, targeting carriers based on (((S)-5-((S)-2-((1r,4S)-4-(aminomethyl)cyclohexane-1-carboxamido)-3-(naphth-2-yl)propamido)-1-carboxypentyl)carbamoyl)-L-glutamic acid, which are derivatives of PSMA-617 or Vipivotide tetraxetan. This PSMA targeting carrier is referred to herein as dPSMA-617 (representing "a derivative of PSMA-617").

[0244] An alternative PSMA targeting vector is (((S)-5-amino-1-carboxypentyl)carbamoyl)-L-glutamic acid (KUE).

[0245] The structures of dPSMA-617 and KUE are in Figure 4 As shown in the image.

[0246] In such embodiments, the KUE or dPSMA-617 conjugated zwitterionic metal chelator comprises 1 to 4 zwitterionic groups. In some specific embodiments, the KUE or dPSMA-617 conjugated zwitterionic metal chelator comprises 1 to 3 zwitterionic groups.

[0247] In some specific implementations, the KUE or PSMA-617 conjugated zwitterionic metal chelating agent has the following formula:

[0248] In one specific implementation, the KUE or PSMA-617 conjugated zwitterionic metal chelator can be combined with Ga 3+ Cu 2 + Lu 3+ Zr 4+ Mn 2+ Mn 3+ 、Tb 3+ Gd 3+ Or similar metal cation complexes.

[0249] Generally, the structure of octreotide (SEQ ID No: 5) is: , or its derivatives.

[0250] Generally, the structure of bufotoxin (SEQ ID No: 6) is: , or its derivatives.

[0251] The synthetic scheme described in Scheme 2 can be used to generate conjugated zwitterionic metal chelators based on DOTA, NOA, porphyrin, deferoxamine, and Py3CA using cRGD, a molecule targeting FAP, octreotide, or a dimer comprising a combination of cRGD, dPSMA-617, a molecule targeting FAP, octreotide, and bufotoxin. In some embodiments, the targeting ligand comprises one or more of the following: having The LyP-1 peptide, which contains the sequence and binds to P32, is used for the diagnosis / treatment of melanoma; it has... The K237 peptide, which contains the sequence and binds to VEGFR-2, is used for the diagnosis / treatment of breast tumors; it has The IL4RPep-1 peptide, which contains the sequence of IL4R and binds to IL4R, is used for the diagnosis / treatment of lung cancer, breast cancer, and colon cancer; it has... The mUNO peptide, which binds to CD206, is used for the diagnosis / treatment of breast cancer; the folate receptor, used for the diagnosis / treatment of ovarian and lung cancer; and the dodecapeptide GE11, which binds to the epidermal growth factor receptor (EGFR or ErbB1), used for the diagnosis / treatment of epithelial-derived tumors. Depending on the reactive group of the zwitterionic metal chelator, other common chemical methods can be used to conjugate the targeting carrier, such as azide-alkyne cycloaddition, nucleophilic substitution, Diels-Alder reaction, urea and carbamate formation, thiol-ene conjugation, or similar transformations. For some of these transformations, derivatives of KUE or dPSMA-617 with other reactive functional groups can be used. For example, conjugation via copper-catalyzed azide-alkyne cycloaddition may require an alkyne or azide group as the reactive group on the zwitterionic chelator and a matching alkyne or azide group as the reactive group on the targeting carrier.

[0252] In some embodiments, the targeting ligand may also include a molecular scaffold portion that can be linked to the binding portion and other groups. For example, the molecular scaffold may carry one or more of the following: (1) a portion designed to react with the reactive linking group of the dye to form a covalent bond, (2) a charge-balancing portion, such as any ionic group described herein, and (3) a portion that binds to the biological target. An example of a molecular scaffold is an adamantane derivative, such as described in U.S. Patent Application Publication No. 2006 / 0063834, which is incorporated herein by reference in its entirety and illustrates by way of example the preparation of a targeting ligand incorporated into an adamantane scaffold. In particular, the adamantane core contains (1) an amino group capable of reacting with the dye compound, (2) a charge-balancing portion that neutralizes the negative charge on the dye molecule, and (3) two portions that bind to the biological target PSMA. For a description of the portion that binds to PSMA, see Humblet, V. et al. Mol. Imaging, 2005, 4: 448-62; Misra P. et al. J. Nucl. Med. 2007, 48: 1379-89; Chen, Y., et al. J. Med. Chem, 2008, 51:7933-43; Chandran, SS, et al. Cancer Biol. Ther., 2008, 7:974-82; Banerjee, SR, J. Med. Chem. 2008, 51: 4504-17; Mease, RC, et al. Clin. Cancer Res., 2008, 14:3036-43; Foss, CA et al. Clin. Cancer. Res., 2005, 11:4022-8, each of which is incorporated herein by reference in its entirety.

[0253] Imaging methods

[0254] In one aspect, the present invention provides a method for biomedical imaging of tissues or cells in a biological sample. In one specific embodiment, the present invention covers a method for detecting or imaging one or more types of cancer cells in a biological sample.

[0255] In some implementations, the method is suitable for imaging abnormal but non-malignant tissues, such as musculoskeletal system defects using FAP as a target carrier or vascular system defects using cRGD as a target carrier.

[0256] In some embodiments, the method is suitable for imaging cancer, tumors, or growths. In another embodiment, the cancer is selected from ocular cancer or eye cancer, rectal cancer, colon cancer, cervical cancer, prostate cancer, breast cancer and bladder cancer, oral cancer, benign and malignant tumors, gastric cancer, liver cancer, pancreatic cancer, lung cancer, uterine cancer, ovarian cancer, prostate cancer, testicular cancer, kidney cancer, brain / cns cancer (e.g., glioma), laryngeal cancer, skin melanoma, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing sarcoma, Kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, angiosarcoma, hemangioendothelioma, nephroblastoma, neuroblastoma, oropharyngeal cancer, esophageal cancer, laryngeal cancer, lymphoma, neurofibromatosis, tuberous sclerosis, hemangioma, and lymphangiogenesis.

[0257] In some implementations, the cancer cells are adult solid tumor cells or pediatric solid tumor cells. Some non-limiting examples of such cells include melanoma cells, neuroblastoma cells, lung cancer cells, adrenal cancer cells, colon cancer cells, colorectal cancer cells, ovarian cancer cells, prostate cancer cells, liver cancer cells, subcutaneous cancer cells, squamous cell carcinoma cells, colon cancer cells, retinoblastoma cells, cervical cancer cells, glioma cells, breast cancer cells, pancreatic cancer cells, Ewing sarcoma cells, rhabdomyosarcoma cells, osteosarcoma cells, retinoblastoma cells, nephroblastoma cells, and pediatric brain tumor cells.

[0258] In some specific implementation schemes, the cancer cells are prostate cancer cells.

[0259] In some implementations, the biological sample is part or all of the object. In some implementations, the biological sample is obtained from the object.

[0260] In some specific embodiments, the method includes (a) contacting a biological sample with one or more of the above-described zwitterionic metal chelating agents, wherein the zwitterionic metal chelating agent is coordinated with metal atoms that can be detected by one or more conventional scanning methods.

[0261] In some embodiments, the compound is administered via parenteral, intranasal, sublingual, rectal, or percutaneous delivery. In some such embodiments, the compound is administered intravenously. In some embodiments, the compound is administered intratumorally.

[0262] In some embodiments, a tumor or cells are present in the object. The object to be treated by the methods of this disclosure is expected to be a human object in many embodiments; however, it should be understood that the methods described herein are effective for all vertebrate species intended to be included in the term "object." Thus, "object" can include: human objects for medical purposes, such as for the treatment of an existing symptom or disease or for preventative treatment to prevent the onset of a symptom or disease; or animal (non-human) objects for medical, veterinary, or developmental purposes. Suitable animal subjects include mammals, including but not limited to: primates, such as humans, monkeys, and apes; bovines, such as cattle and oxen; ovines, such as sheep; caprines, such as goats; porcines, such as pigs and hogs; equines, such as horses, donkeys, and zebras; felines, including wild and domestic cats; canines, including dogs; lagomorphs, including rabbits and hares; and rodents, including mice and rats. Animals may be transgenic animals. In some embodiments, the subject is a human being, including but not limited to fetuses, newborns, infants, adolescents, and adults. Furthermore, "subject" may include patients who have or are suspected of having a condition or disease. Therefore, the terms "subject" and "patient" are used interchangeably herein. In some embodiments, the subject is a human being. In other embodiments, the subject is a non-human being.

[0263] In some specific implementation plans, the target is people.

[0264] Methods for imaging tissues or cells include the following basic steps:

[0265] (a) Contacting tissues or cells with a developing agent containing a zwitterionic metal chelating agent; and

[0266] (b) Imaging tissues or cells using positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI).

[0267] The imaging agents described herein are substances that can be used to image tissues or cells (e.g., tissues or cells of a living organism) for purposes such as diagnosis, treatment, and image-guided surgery. In some embodiments, the organism is a mammal, such as a human.

[0268] The imaging agents described herein generally exhibit an improved signal-to-background ratio (SBR) compared to currently known imaging agents. This improvement in SBR is considered a result of improved in vivo properties due to "charge balance." SBR is a measure of the intensity of a signal (peak signal) obtained from a target relative to the intensity of a signal (background signal) obtained near the target, which is the tissue or cells targeted by the imaging agent. SBR measurements can be readily obtained using standard measurement procedures. Higher SBR values ​​are more desirable, resulting in higher resolution imaging of the tissue. In some embodiments, the imaging agent achieves an SBR of at least about 1.1 (i.e., the peak signal is at least 10% higher than the background). In other embodiments, the imaging agent achieves an SBR of at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, or at least about 2.0. In yet other embodiments, the developer achieves an SBR of about 1.1 to about 50, about 1.5 to about 30, about 2.0 to about 20, about 2.0 to about 5.0, or about 5.0 to about 10.

[0269] The zwitterionic metal chelating agents of the present invention generally have good solubility in substantially neutral aqueous media, and particularly, good solubility in blood or serum. In some embodiments, the developer has a solubility of at least about 10 μM in a 10 mM HEPES solution at pH 7.4. In other embodiments, the developer has a solubility of at least about 15 μM, at least about 20 μM, at least about 25 μM, at least about 30 μM, at least about 40 μM, or at least about 50 μM in a 10 mM HEPES solution at pH 7.4.

[0270] The zwitterionic metal chelates of the present invention exhibit significantly improved stability over time, allowing for significantly improved operability and use in imaging and mapping. Similarly, the stability of the imaging agent allows for improved accuracy during surgery because the signal does not fade over time. This is particularly important for Gd complexes used as MRI contrast agents. Long-term accumulation of Gd has been identified due to its instability in its metal chelates and / or inefficient clearance from the body. The zwitterionic metal chelates of Gd address this problem by maximizing the stability of the metal complexes while simultaneously maximizing rapid clearance from the body via renal renal elimination.

[0271] In another aspect, this disclosure covers methods for measuring and / or monitoring the effectiveness of various biological functions of a subject. In some specific embodiments, methods are provided for measuring the effectiveness of liver function, kidney function, or blood pooling in a subject. In such embodiments, zwitterionic metal chelators may be used with or without the addition of a targeting carrier. The method includes the steps of: administering a quantifiable amount of one or more of the aforementioned zwitterionic metal chelators to a subject whose biological function needs to be measured; imaging the subject using positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); and determining the amount of zwitterionic metal chelator present in the observed biological function.

[0272] Treatment, diagnosis and monitoring methods

[0273] Cancer

[0274] In another aspect, this disclosure covers methods for inhibiting the proliferation or growth of malignant or non-malignant cells. The method includes the step of contacting one or more cells with an effective amount of one or more of the aforementioned zwitterionic metal chelating agents, wherein the metal atom is a radioactive metal isotope known to emit ionizing radiation in a form that causes cell death upon uptake of the analogue.

[0275] Some non-limiting examples of metal isotopes used include Lu-177, Y-90, Ho-166, Re-186, Re-188, Cu-67, Au-199, Rh-105, Ra-223, Ac-225, As-211, Pb-212, and Th-227.

[0276] In some implementations, the method is performed in vivo, in vitro, or outside the body.

[0277] In some implementations, the malignant cells are adult solid tumor cells or pediatric solid tumor cells. Some non-limiting examples of such cells include melanoma cells, neuroblastoma cells, lung cancer cells, adrenal cancer cells, colon cancer cells, colorectal cancer cells, ovarian cancer cells, prostate cancer cells, liver cancer cells, subcutaneous cancer cells, squamous cell carcinoma cells, colon cancer cells, retinoblastoma cells, cervical cancer cells, glioma cells, breast cancer cells, pancreatic cancer cells, Ewing sarcoma cells, rhabdomyosarcoma cells, osteosarcoma cells, retinoblastoma cells, nephroblastoma cells, and pediatric brain tumor cells.

[0278] In another aspect, this disclosure covers methods for diagnosing cancer in a subject. These methods include one or more of the imaging / detection steps outlined above. In these methods, a biological sample is obtained from a portion or all of the subject. If cancer cells are detected or imaged during these method steps, the subject is diagnosed with cancer. In some embodiments, the method for diagnosing cancer in a subject is followed by a step of treating the subject diagnosed with cancer with cancer. In some embodiments, the cancer treatment is surgery, chemotherapy, or radiation therapy.

[0279] In some implementation schemes, the diagnosed cancer is an adult solid tumor or a pediatric solid tumor. Some non-limiting examples of such cancers include melanoma, neuroblastoma, lung cancer, adrenal cancer, colon cancer, colorectal cancer, ovarian cancer, prostate cancer, liver cancer, subcutaneous cancer, squamous cell carcinoma, bowel cancer, retinoblastoma, cervical cancer, glioma, breast cancer, pancreatic cancer, Ewing sarcoma, rhabdomyosarcoma, osteosarcoma, retinoblastoma, nephroblastoma, and pediatric brain tumors.

[0280] In another aspect, this disclosure covers a method for monitoring the efficacy of cancer treatment in human subjects. The method includes performing one or more of the outlined imaging / detection steps on a biological sample at two or more different time points, wherein the biological sample is obtained from a portion or all of the subject. Changes in the intensity of the signal characteristics of a metal isotope between the two or more different time points are correlated with the efficacy of the cancer treatment.

[0281] In another aspect, this disclosure covers methods for treating abnormal but non-malignant tissues, such as musculoskeletal system defects using FAP as a target carrier or vascular system defects using cRGD as a target carrier. The method includes the step of contacting one or more abnormal cells with an effective amount of one or more of the aforementioned zwitterionic metal chelating agents, wherein the metal atom is a radioactive metal isotope known to emit ionizing radiation in a form that produces a therapeutic effect on cells that take up the analogue.

[0282] In another aspect, this disclosure covers a method for treating cancer by administering an effective amount of a therapeutic agent comprising a zwitterionic metal chelating agent complex and a pharmaceutically acceptable carrier or excipient. The method includes the steps of diagnosing cancer and administering the therapeutic agent to a subject determined to have this need.

[0283] The steps involved in diagnosing cancer include:

[0284] To bring the subject's cells, tissues, or organs into contact with the imaging agent.

[0285] The cells, tissues, or organs of the subject are imaged using positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI), and

[0286] Diagnose cancer in the cells, tissues, or organs of the subject based on the collected imaging data;

[0287] Furthermore, the metal atoms that are complexed with the zwitterionic metal chelating agent are:

[0288] A known radioactive metallic isotope emits ionizing radiation, which causes cell death upon ingestion of the analogue.

[0289] Or non-radioactive metals that can release cytotoxic radiation after irradiation with alpha radiation, beta radiation, neutron capture, or a combination thereof.

[0290] In another aspect, this disclosure covers methods for treating rare or pediatric cancers by administering an effective amount of a therapeutic agent comprising a zwitterionic metal chelating agent complex and a pharmaceutically acceptable carrier or excipient. In such an aspect, the therapeutic agent may also comprise one or more targeting carriers selected from cRGD, PSMA, FAP, octreotide, bufotoxin, or homo or hetero oligomers formed from combinations thereof.

[0291] In some implementations, the targeting ligand includes one or more of the following: having The LyP-1 peptide, which contains the sequence and binds to P32, is used for the diagnosis / treatment of melanoma; it has... The K237 peptide, which contains the sequence and binds to VEGFR-2, is used for the diagnosis / treatment of breast tumors; it has The IL4RPep-1 peptide, which contains the sequence of IL4R and binds to IL4R, is used for the diagnosis / treatment of lung cancer, breast cancer, and colon cancer; it has... The sequence of the mUNO peptide, which binds to CD206, is used for the diagnosis / treatment of breast cancer; the folic acid receptor, used for the diagnosis / treatment of ovarian and lung cancer; and the dodecapeptide GE11, which binds to the epidermal growth factor receptor (EGFR or ErbB1), is used for the diagnosis / treatment of epithelial-derived tumors. Additionally, the metal atom complexed with the zwitterionic metal chelator is:

[0292] A known radioactive metallic isotope emits ionizing radiation, which causes cell death upon ingestion of the analogue.

[0293] Or non-radioactive metals that can release cytotoxic radiation after irradiation with alpha radiation, beta radiation, neutron capture, or a combination thereof.

[0294] In some specific implementation plans, rare or childhood cancers include: acinar cell carcinoma, ACTH-secreting tumors, actinic keratosis, ameloblastoma, adenoid cystic carcinoma, acinar soft tissue sarcoma, ampullary carcinoma, angiosarcoma, neuroendocrine (carcinoid) tumor of the appendix, Askin's tumor—a type of Ewing tumor (Ewing sarcoma), Bartholin's adenocarcinoma, basaloid squamous cell carcinoma of the anus, Bowen's disease, bronchioloalveolar carcinoma, carcinoid tumor, ampullary carcinoma of Vater, cardiac angiosarcoma, and Castleman's disease. Diseases, bile duct cancer, choriocarcinoma, choroid plexus tumors, chondrosarcoma, chordoma, chromophobe renal cell carcinoma, clear cell sarcoma, craniopharyngioma, dermatofibrosarcoma protuberans, desmoidoma, connective tissue proliferative small round cell tumor, dysgerminoma, embryonal carcinoma, endodermal sinus tumor, endometrial stromal sarcoma, ependymoma, epithelial appendix (appendix) carcinoma, epithelial-myoepithelial carcinoma, epithelioid hemangioendothelioma (EHE), epithelioid sarcoma, essential thrombocytosis, sensory neuroblastoma (olfactory neuroblastoma), extracranial malignant rhabdoid tumor Tumor (MRT), extranodal NK / T-cell lymphoma - nasal type, fallopian tube carcinoma, fibrolamellar carcinoma, fibromatosis, fibromyxoid sarcoma (Evans tumor), fibrosarcoma follicular mycosis fungoides, ganglion cell glioma, ganglion cell neuroblastoma, gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS), gastrinoma, gastroesophageal junction (GEJ) carcinoma, gestational trophoblastic disease (GTD) (hydatidiform mole; gestational trophoblastic tumor), germ cell tumor, giant cell tumor of bone, glucagonoma, granulomatous cutis laxa, cardiac cancer (cardiac angiosarcoma), hemangioendothelioma, angiosarcoma, hepatobiliary cancer, hepatoblastoma, hepatocellular carcinoma, liver cancer, hereditary diffuse gastric cancer,HDGC), Hurthle cell cancer (eosinophilic cell carcinoma), insulinoma, islet cell tumor, keratoacanthoma, Klatskin tumor, large cell neuroendocrine carcinoma, leiomyosarcoma, testicular interstitial cell tumor, lip cancer, liposarcoma, lymphomatoid papulosis, lymphoplasmacytic lymphoma, malignant mesenchymal tumor, malignant mixed Miller tumor, malignant peripheral nerve sheath tumor (MPNST), malignant rhabdomyosarcoma of the kidney, medullary epithelioma, meningioma, mesodermal nephroma, breast metaplastic carcinoma, monoclonal gammopathy of undetermined significance. Significance, MGUS), oral cancer, mucinous cystic tumor, mucinous epidermoid carcinoma, muscle cancer (sarcoma), myoepithelial carcinoma, mycosis fungoides, myelofibrosis, myxofibrosarcoma, nephroblastoma, cutaneous neuroendocrine carcinoma, NUT carcinoma, oat cell carcinoma, occult primary cancer, ocular or intraocular melanoma, olfactory neuroblastoma (sensory neurocytoma), oligodendroglioma, eosinophilic cell carcinoma, small cell ovarian carcinoma, Paget's disease, Paget's reticulum cellulosis, paraganglioma, parathyroid carcinoma, periosteal osteosarcoma, peripheral primitive neuroectodermal tumor. Tumors (PPNET), pheochromocytoma, phyllodes tumors, pineal blastoma, plasmacytoma, polycythemia vera, pleomorphic low-grade adenocarcinoma, primary cutaneous lymphoma, primary peritoneal cancer, prolactinoma (prolactin-secreting adenoma), renal cell carcinoma, sarcomatoid carcinoma (carcinosarcoma), schwannoma, sclerosing epithelioid fibrosarcoma, sebaceous gland carcinoma, seminoma, Sertoli cell carcinoma of the testis, Sezary syndrome. Syndrome), sinus cancer, skin and appendage tumors, solid pseudopapillary tumor, solitary fibrous tumor, solitary plasmacytoma, somatostatinoma, seminoma, spindle cell tumor, spindle cell carcinoma, spindle cell sarcoma, subcutaneous panniculitis-like T-cell lymphoma, synovial sarcoma, T-cell lymphoma, teratoma, laryngeal cancer, thymoma, tongue cancer, tonsil cancer, trabecular carcinoma, translocated renal cell carcinoma, transitional cell carcinoma (urothelial carcinoma), undifferentiated pleomorphic sarcoma, urachal carcinoma, urethral cancer, urothelial carcinoma (transitional cell carcinoma), uterine cancer, verrucous carcinoma, vasodilator endothelioma, vocal cord / larynx cancer, uterine sac cancer, or yolk sac tumor.

[0295] Non-cancerous conditions

[0296] In another aspect, the present invention provides a method for treating a non-cancerous condition in a subject with this need, the method comprising: administering an effective amount of a therapeutic agent to the subject, said therapeutic agent comprising a zwitterionic metal chelating agent complex and a pharmaceutically acceptable carrier or excipient. In some embodiments, the metal atom complexed with the zwitterionic metal chelating agent is:

[0297] A known radioactive metallic isotope emits ionizing radiation, which results in a therapeutic effect on the object.

[0298] Or a non-radioactive metal that can release therapeutic radiation after irradiation with alpha radiation, beta radiation, neutron capture, or a combination thereof.

[0299] In some implementations, the noncancerous condition is a musculoskeletal disorder or a tissue hypertrophy disorder. In other implementations, the noncancerous condition is myocardial infarction, atherosclerosis, or fibrositis (including, but not limited to, interstitial lung disease, rheumatoid arthritis, liver fibrosis, and keloids).

[0300] In other implementations, the object is a person.

[0301] Measurement of the effectiveness of biological systems.

[0302] In another aspect, this disclosure covers methods for measuring the efficacy of a biological system. In some specific embodiments, the biological system to be measured or monitored is the renal system, hepatic system, or blood pool.

[0303] In some specific implementation schemes, methods for measuring the efficacy of biological systems include:

[0304] (a) Administering a quantifiable amount of a diagnostic agent to a subject, the diagnostic agent comprising a zwitterionic metal chelating agent complex and a pharmaceutically acceptable carrier or excipient;

[0305] (b) Imaging the subject using positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); and

[0306] (c) Determine the amount of therapeutic agent present in the biological system observed in the object.

[0307] In one specific aspect, this disclosure covers a method for measuring the efficacy of renal function in a subject. In some specific embodiments, the method includes:

[0308] (a) Administering a quantifiable amount of a diagnostic agent to a subject, the diagnostic agent comprising a zwitterionic metal chelating agent complex and a pharmaceutically acceptable carrier or excipient;

[0309] (b) Imaging the subject using positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); and

[0310] (c) Determine the amount of therapeutic agent present in the biological system observed in the object.

[0311] In another aspect, the present invention provides a method for quantifying the glomerular filtration rate of a subject. In some specific embodiments, the method includes:

[0312] (a) Administering a quantifiable amount of a diagnostic agent to a subject, said diagnostic agent comprising a zwitterionic metal chelating agent complex and a pharmaceutically acceptable carrier or excipient; and

[0313] (b) Using measurements of each bodily fluid or imaging the subject with positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI), determine the amount of diagnostic agent present in the subject's blood and urine as a function of time.

[0314] Radiation surgery

[0315] Radiosurgery is a known method for treating targets within the body. During radiosurgery, a series of X-ray beams emitted from multiple different locations and directions are used to bombard the target using a radiation delivery system, influencing tumor biology using the cumulative radiation dose at the target. Radiation can be delivered invasively, either in conjunction with conventional scalpel surgery or via percutaneous catheters. CyberKnife™ (Accuray Inc.) and Trilogy™ (Varian Medical Systems) are two such radiation delivery systems. Advances in stereotactic surgery have provided improved accuracy in aligning the target tissue and the location of the radiation source for treatment. See, for example, U.S. Patent Nos. 6,351,662 and 6,402,762. Stereotactic radiosurgery systems are commercially available from ACCURAY, INC. and BRAINLAB in Sunnyvale, Calif. The AccurayCyberknife™ stereotactic radiosurgery system has been reported for providing targeted, painless, and rapid cancer treatment.

[0316] In one aspect, the present invention provides a radiosurgical method for treating a patient's body, the method comprising:

[0317] Receive the desired lesion pattern and planned radiation distribution;

[0318] The diagnostic agent, comprising a zwitterionic metal chelating agent complex and a pharmaceutically acceptable carrier or excipient, is administered to the subject in an effective amount to efficiently image a desired lesion pattern; and the diagnostic agent is administered to the subject in an effective amount to image a desired lesion pattern.

[0319] To treat the patient's body by performing surgery on the desired lesion pattern.

[0320] In some implementations, the surgery may be performed using a scalpel or a stereotactic radiosurgery system to deliver a cumulative radiation dose.

[0321] In other embodiments, the zwitterionic metal chelator of the diagnostic agent further comprises one or more targeting carriers, wherein the one or more targeting carriers are cRGD, KUE, dPSMA-617, molecules targeting FAP, octreotide, bufotoxin, or homo or hetero oligomers formed from combinations thereof. In some embodiments, the targeting ligand comprises one or more of the following: The LyP-1 peptide, which contains the sequence and binds to P32, is used for the diagnosis / treatment of melanoma; it has... The K237 peptide, which contains the sequence and binds to VEGFR-2, is used for the diagnosis / treatment of breast tumors; it has The IL4RPep-1 peptide, which contains the sequence of IL4R and binds to IL4R, is used for the diagnosis / treatment of lung cancer, breast cancer, and colon cancer; it has... The sequence of mUNO peptide, which binds to CD206, is used for the diagnosis / treatment of breast tumors; the folic acid receptor, used for the diagnosis / treatment of ovarian and lung cancer; and the dodecapeptide GE11, which binds to the epidermal growth factor receptor (EGFR or ErbB1), is used for the diagnosis / treatment of epithelial tumors.

[0322] In other implementations, the desired lesion pattern is received from the user interface of the treatment planning module. Such a planning module can be pre-programmed with instructions for various disease states and cancerous features. Alternatively, artificial intelligence data can be used to identify and generate instructions for the desired lesion pattern.

[0323] Toxic metals

[0324] The zwitterionic metal chelating agents described herein can also be used as a treatment for removing toxic or excess metals from a subject. In such a method, the zwitterionic metal chelating agent is administered in the absence of a metal to which it is coordinated. The chelating agent binds to excess or toxic metals in the subject, which are subsequently cleared along with the chelating agent via the kidneys and renal system. The use of zwitterionic metal chelating agents in this method allows for faster removal of excess metals from the subject, with increased clearance time and reduced damage to the liver and other organs.

[0325] Therefore, in one aspect, this disclosure covers a method for removing toxic or excessive metals from an object requiring such treatment, the method comprising:

[0326] (a) Administering a therapeutically effective amount of the treatment agent to the subject,

[0327] The therapeutic agent comprises a metal chelating agent having one or more zwitterionic groups not coordinated with a metal or metal isotope, and a pharmaceutically acceptable carrier or excipient.

[0328] In some embodiments, the metal chelating agent in the therapeutic agent has the following formula:

[0329] In other implementations, the toxic or excessive metals are lead, mercury, arsenic, cadmium, thallium, iron, zinc, chromium, manganese, aluminum, cobalt, selenium, beryllium, lithium, silver, or tin.

[0330] In other implementations, the toxic or excessive metals are lead, mercury, arsenic, cadmium, thallium, iron, zinc, chromium, manganese, aluminum, cobalt, selenium, beryllium, lithium, silver, or tin.

[0331] Other applications – agricultural and chemical processes

[0332] Zwitterionic metal chelators improve solubility and minimize nonspecific interactions. These improved properties are thought to result from the balance of formal charges on the metal chelator, which gives multiionic but “charge-balanced” molecules a neutral or near-neutral net charge, resulting in an expanded hydration layer and better metal separation.

[0333] The zwitterionic metal chelators described herein can also be used in agricultural systems. In some specific embodiments, the zwitterionic metal chelators described herein can be used to supply micronutrients (trace metals, such as iron, zinc, manganese, and copper) to a variety of crops and plants. These micronutrients can help prevent drought and other diseases, particularly those caused by the overuse of certain fertilizers (especially phosphate fertilizers). Similarly, the zwitterionic metal chelators described herein can be used to supply a variety of herbicides that are otherwise insoluble.

[0334] Similarly, the zwitterionic metal chelators described herein can also be used in chemical processes. Due to exposure to the toxic metals described herein, certain chemical processes require chelation and removal of excess metals, such as metal catalysts. Therefore, the zwitterionic metal chelators described herein can also be used in such chemical processes to remove insoluble metal impurities and / or unwanted metal components.

[0335] In particular, the zwitterionic metal chelators described herein have an advantage over conventional metal chelators in terms of the polarity of the zwitterionic molecules. Due to this polarity, the zwitterionic metal chelators described herein can be used in aqueous solutions, for example, to increase the solubility of metals, and can subsequently be precipitated from solution by adding a less polar solvent. This precipitation allows for the capture and subsequent disposal of undesirable metals, such as iron capture from wastewater (urban mining). In other embodiments, precipitation of the zwitterionic metal chelators containing sulfobetaine described herein can be induced by the addition of a salt.

[0336] Dosage form and administration method

[0337] In some methods of the present invention, the zwitterionic metal chelating agent is administered at a predetermined dose. There is no particular limitation on the amount of the predetermined dose, provided that it is administered at least the minimum amount that can be cleared by the kidneys within twelve hours. In some specific embodiments using non-radioactive techniques, the predetermined dose is 0.5 mg / kg body weight; 0.25 mg / kg body weight; 0.1 mg / kg body weight; 0.05 mg / kg body weight; 0.01 mg / kg body weight; 0.005 mg / kg body weight; or 0.001 mg / kg body weight. In other embodiments, the predetermined dose is 5.0 mg; 2.5 mg; 1.0 mg; 0.75 mg; 0.5 mg; 0.25 mg; or 0.1 mg. In some specific embodiments using radioactive techniques, the dose will be subject to dose-limiting toxicity. Generally, the effective dose for imaging will be 0.1 mCi to 20 mCi, and the effective dose for treatment will be 0.1 to 10 mCi / kg.

[0338] In some embodiments, a detectable effective amount of the zwitterionic metal chelating agent of the method of this disclosure is administered to the subject. According to the subject matter of this disclosure, a “detectable effective amount” of the imaging agent is defined as an amount sufficient to produce acceptable images using a clinically usable device. A detectable effective amount of the agent can be administered in more than one injection. The detectable effective amount of the imaging agent can vary depending on factors such as: individual susceptibility, individual age, sex, and weight, individual idiosyncratic response, dosing, and instrument and film-related factors. Optimization of such factors is entirely within the scope of the art.

[0339] The reagents of this invention can be administered by any of the means described herein and are generally acceptable to patients and those skilled in the art. In particular, the charge balance imaging agent is administered intravenously.

[0340] The predetermined target dose depends on a variety of factors, including but not limited to the type of tumor or lesion to be observed and the location of any cells to be imaged. Therefore, the predetermined dose is set by a person skilled in the art before administering the reagent. Such factors include, but are not limited to, the amount determining the dose, the patient's height, weight, age, body mass index, and sex, or any combination thereof.

[0341] In some specific embodiments using non-radioactive techniques, when the amount of the predetermined dose is from about 2.5 mg to about 5.0 mg or greater, the predetermined target amount is 50% of the amount of the predetermined dose. In other embodiments, when the amount of the predetermined dose is from about 0.5 mg to about 2.5 mg, the predetermined target amount is 60% of the amount of the predetermined dose. In still other embodiments, when the amount of the predetermined dose is about 0.5 mg or less, the predetermined target amount is 80% of the amount of the predetermined dose.

[0342] Any route of administration may be suitable for administering the disclosed reagent to a subject. In one embodiment, the disclosed zwitterionic metal chelator may be administered to the subject via intravenous injection. In another embodiment, the disclosed zwitterionic metal chelator may be administered to the subject via any other suitable systemic delivery method, such as parenteral, intranasal, sublingual, rectal, or percutaneous administration.

[0343] In another embodiment, the disclosed zwitterionic metal chelating agent can be administered to the subject via intraperitoneal injection or intraperitoneal injection (IP).

[0344] In another embodiment, the disclosed zwitterionic metal chelating agent can be administered to the subject via intratumoral injection.

[0345] For the use of neutron capture therapy to treat non-malignant or malignant tissues, the target is bombarded with neutrons of appropriate energy after the application of (usually targeted) zwitterionic chelators and sufficient time for biodistribution, binding, and clearance of unbound doses.

[0346] This disclosure also includes methods of using pharmaceutical compositions comprising one or more of the disclosed zwitterionic metal chelators associated with a pharmaceutically acceptable carrier. Preferably, these compositions are administered in unit dosage forms for parenteral, intranasal, sublingual, or rectal administration, or for administration by inhalation or blowing, such unit dosage forms include: tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosols or liquid sprays, drops, ampoules, auto-injector devices, or suppositories.

[0347] For the preparation of solid compositions (e.g., tablets), the main active ingredient is mixed with a pharmaceutically acceptable carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, or gum) and other pharmaceutically acceptable diluents (e.g., water) to form a solid preformed composition comprising a homogeneous mixture of the zwitterionic metal chelating agent of the present invention or its pharmaceutically acceptable salt. When these preformed compositions are referred to as homogeneous, it means that the active ingredient is uniformly dispersed throughout the composition, such that the composition can be readily further divided into equivalent unit dosage forms, such as tablets, pills, and capsules. The solid preformed composition is then further divided into unit dosage forms of the type described above, containing 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain 1 to 100 mg, for example 1, 2, 5, 10, 25, 50, or 100 mg of the active ingredient. The tablets or pills of the new composition may be coated or otherwise compounded to provide a dosage that offers the advantage of prolonged action. For example, tablets or pills may contain an internal dose and an external dose component, the latter being a coating that covers the former. These two components can be separated by an enteric coating, which resists disintegration in the stomach and allows the internal component to enter the duodenum intact or delays release. A variety of materials can be used for such an enteric coating or coating, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0348] The liquid forms in which zwitterionic metal chelators can be incorporated for oral or injectable administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils (e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical carriers. Suitable dispersants or suspending agents for aqueous suspensions include synthetic and natural gums, such as gum arabic, gum arabic, alginate / esters, dextran, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone, or gelatin.

[0349] The disclosed zwitterionic metal chelators are particularly useful when formulated in pharmaceutically injectable doses, including in combination with injectable carrier systems. Injectable and infusion dosage forms (i.e., parenteral dosage forms) used herein include, but are not limited to, liposomal injectables or phospholipid bilayer vesicles encapsulating active pharmaceutical substances. Injectables comprise sterile formulations intended for parenteral use.

[0350] There are five distinct categories of injectable preparations as defined by the USP: emulsions, lipids, powders, solutions, and suspensions. Emulsion injections comprise emulsions containing sterile, pyrogen-free formulations intended for parenteral administration. Lipid complexes and powders for solution injections are sterile formulations designed to be reconstituted for parenteral use. Powders for suspension injections are sterile formulations designed to be reconstituted for parenteral use. Lyophilized powders for liposome suspension injections are sterile, lyophilized formulations designed to be reconstituted for parenteral use, formulated in a manner that allows incorporation of liposomes (e.g., lipid bilayer vesicles with phospholipids for encapsulating active pharmaceutical ingredients within a lipid bilayer or an aqueous space), thereby forming the formulation after reconstitution. Lyophilized powders for solution injections are dosage forms intended for use in solutions, prepared by lyophilization (“lyophilization”), a process involving the removal of water from a frozen product under extremely low pressure, thereby resulting in a solution that meets all requirements for injection. Lyophilized powders for use as suspension injections are liquid formulations intended for parenteral use, comprising a solid suspended in a suitable fluid medium, and meeting in all respects the requirements of a sterile suspension. Thus, reagents intended for use as suspensions are prepared by lyophilization. Solution injections involve liquid formulations comprising one or more pharmaceutical substances dissolved in a suitable solvent or a mixture of mutually miscible solvents suitable for injection.

[0351] Solution concentrate injections relate to sterile preparations for parenteral use, which, upon addition of a suitable solvent, produce a solution that meets injectability requirements in all respects. Suspension injections relate to liquid preparations (suitable for injection) comprising solid particles dispersed throughout a liquid phase, wherein said particles are insoluble, and wherein an oil phase is dispersed throughout an aqueous phase, and vice versa. Liposome suspension injections are liquid preparations (suitable for injection) having an oil phase dispersed throughout an aqueous phase in such a manner as to form liposomes (typically lipid bilayer vesicles containing phospholipids for encapsulating active pharmaceutical ingredients within a lipid bilayer or aqueous space). Acoustically treated suspension injections are liquid preparations (suitable for injection) comprising solid particles dispersed throughout a liquid phase, wherein said particles are insoluble. Additionally, the product can be acoustically treated by passing gas bubbles through the suspension, resulting in the formation of microspheres from the solid particles.

[0352] Parenteral carrier systems include one or more pharmaceutically suitable excipients, such as solvents and cosolvents, solubilizers, wetting agents, suspending agents, thickeners, emulsifiers, chelating agents, buffers, pH adjusters, antioxidants, reducing agents, antimicrobial preservatives, bulking agents, protectants, tension modifiers, and special additives.

[0353] The present invention also provides packaged pharmaceutical compositions comprising a pharmaceutically acceptable carrier and the zwitterionic metal chelating agent of the present invention. In some embodiments, the packaged pharmaceutical composition will contain a reaction precursor necessary for generating the zwitterionic metal chelating agent of the present invention after combination with a metal or radiolabeled precursor.

[0354] This invention also allows zwitterionic metal chelators to be provided in a non-radioactive “kit” format, comprising a non-radioactive zwitterionic chelator / targeting carrier molecule, a preparation device (e.g., a hot plate), and a quality control device (e.g., a test strip or equivalent). The user adds a radioactive metal to immediately produce the final injectable drug prior to its use as an imaging agent and / or therapeutic agent. In this way, the kit can be prepared and transported in a non-radioactive form, with the radioactive metal added on-site. The non-radioactive zwitterionic chelator / targeting carrier molecule can be provided in solution or lyophilized form. When the carrier and imaging agent of the kit are in lyophilized form, the kit may optionally contain a sterile and physiologically acceptable remodeling medium, such as water, saline, buffered saline, etc.

[0355] This kit can provide the zwitterionic metal chelating agent of the present invention in solution or lyophilized form, and these components of the kit may optionally include stabilizers such as NaCl, silicates, phosphate buffers, ascorbic acid, gentian acid, etc. Further stabilizing effects of the kit components can be provided in this embodiment, for example by providing a reducing agent in an antioxidant form.

[0356] The determination and optimization of such stabilizers and stabilization methods are entirely within the scope of the art. When the targeting molecule / chelating agent of this embodiment is in lyophilized form, the kit may optionally contain sterile and physiologically acceptable remodeling media, such as water, saline, buffered saline, etc. The amounts of the unlabeled targeting molecule / chelating agent, auxiliary molecule, and reducing agent in this embodiment are optimized according to the method described above for preparing cardiovascular imaging agents. A radionuclide may be combined with the unlabeled targeting molecule / chelating agent and reducing agent at a time and temperature sufficient to chelate the radionuclide with the targeting molecule / chelating agent, and the resulting imaging agent may be injected into the patient.

[0357] Those skilled in the art can use the imaging agent of the present invention according to the method. Images can be generated by means of differences in the spatial distribution of the imaging agent accumulated at the site. Spatial distribution can be measured using any means suitable for a particular marker, such as a gamma camera, PET device, SPECT device, etc. The degree of imaging agent accumulation can be quantified using known methods for quantifying radioactive emission. Particularly available imaging methods employ more than one imaging agent for simultaneous study.

[0358] Typically, diagnostic compositions are administered in a dose that effectively achieves the desired signal intensity for detection. Such a dose can vary depending on the organ or tissue to be imaged and the imaging device used. For example, Zeheer et al., Nature Biotechnology, 19, 1148-1154 (2001) used 0.1 μmol / kg as the dose for the IRDye78 conjugate in vivo. Diagnostic compositions can be administered systemically or locally to the patient's organ or tissue to be imaged, followed by imaging of the patient.

[0359] Preferably, a detectable effective amount of the imaging agent of the present invention is administered to the subject. According to the present invention, a “detectable effective amount” of the imaging agent is defined as an amount sufficient to produce acceptable images using clinically usable equipment. The detectable effective amount of the imaging agent of the present invention can be administered in more than one injection. The detectable effective amount of the imaging agent of the present invention can vary depending on factors such as: individual susceptibility, individual age, sex, and weight, individual idiosyncratic response, and dosing determination. The detectable effective amount of the imaging agent of the present invention can also vary depending on instrument and film-related factors. Optimization of such factors is entirely within the scope of the art.

[0360] The amount of imaging agent used for diagnostic purposes and the duration of the imaging study will depend on the radionuclide used to label the reagent, the patient's weight, the nature and severity of the condition being treated, the nature of the patient's existing therapeutic treatments, and the patient's idiosyncratic response. Ultimately, the attending physician will determine the amount of imaging agent administered to each individual patient and the duration of the imaging study.

[0361] Example

[0362] Example 1: Preparation of zwitterionic metal chelating agents

[0363] 1-Benzyl 4-(tert-butyl)2-hydroxysuccinate 2

[0364]

[0365] Benzyl tert-butyl (S)-2-(tert-butyldimethylsiloxy)succinate 1 (1.78 g, 4.52 mmol, 1.00 equivalent) was added to a solution of TBAF in THF (1 mL solution, 6.78 mL, 6.78 mmol, 1.50 equivalent), and 1 mL of THF was added. The solution was stirred at room temperature for 15 min. CH2Cl2 (25.0 mL) was added, and the solution was washed with brine (20 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was removed under vacuum. The crude product was purified by column chromatography on silica (MN BT25 column, as solution loaded, gradient: PE / EtOAc 5:1 to 0:1). Title compound 2 (1.09 g, 86%) was given as a yellow oil.

[0366] 1-Benzyl-4-(tert-butyl)-2-trifluoromethanesulfonyloxysuccinate 3

[0367]

[0368] 2,6-Lutidine (517 µL, 4.46 mmol, 1.50 equivalent) was added to a solution of 1-benzyl 4-(tert-butyl)-2-hydroxysuccinate 2 (833 mg, 2.97 mmol, 1.00 equivalent) in CH₂Cl₂ (11.9 mL) under a nitrogen atmosphere at 0 °C. A solution of Tf₂O (700 µL, 4.16 mmol, 1.40 equivalent) in CH₂Cl₂ (1.05 mL) was added via a syringe pump (4 mL / h), and the solution was stirred at 0 °C for 50 min. Pentane (60.0 mL) was added, and the solution was washed with a 3:1 mixture of brine and 1 m HCl aqueous solution. The organic phase was dried over Na₂SO₄, filtered, and the solvent was removed under vacuum. The crude product was purified by column chromatography on silica (as a solution loaded in PE / CH2Cl2 1:1 (1 mL), MN column BT15, PE / CH2Cl2 1:1). 1-Benzyl-4-(tert-butyl)-2-trifluoromethanesulfonyloxysuccinate 3 (1.08 g, 89%) was obtained as an orange oil.

[0369] Monosubstituted macrocyclic polyamines (cyclen5)

[0370]

[0371] A solution of 1-benzyl-4-(tert-butyl)-2-trifluoromethanesulfonyloxysuccinate 3 (778 mg, 1.89 mmol, 1.00 equivalent) in CH2Cl2 (8.30 mL) was added dropwise to a solution of macrocyclic polyamine 4 (650 mg, 3.77 mmol, 2.00 equivalent) in CH2Cl2 (44.1 mL) over 30 minutes. The resulting mixture was stirred at room temperature for 22 hours. Et3N (3.11 mL) was added, and the solution was stirred for 10 minutes. All volatiles were removed under vacuum. The resulting crude product was dissolved in EtOAc (120 mL) and washed with H2O (3 × 120 mL) and brine (120 mL). The solvent was removed under vacuum to give title compound 5 (700 mg, 85%) as a colorless oil.

[0372] DOT3AZA1COOH tert-butyl ester 7

[0373]

[0374] A macrocyclic polyamine (150 mg, 345 mol, 1.00 equivalent) was dissolved in MeCN (23.5 mL), and Cs₂CO₃ (426 mg, 1.21 mmol, 3.50 equivalent) was added under nitrogen. Azide-trifluoromethanesulfonate (419 mg, 1.14 mmol, 3.30 equivalent) dissolved in MeCN (11.5 mL) was added dropwise. The resulting mixture was stirred under nitrogen at room temperature for 22 hours. The suspension was filtered, and the solvent was removed under vacuum. The crude product was purified by column chromatography on silica (loaded as solution in CH₂Cl₂ (1.5 mL), MN column BT15, gradient: CH₂Cl₂ / MeOH 100:0 to 99:1 to 98:2). The title compound (79 mg, 21%) was obtained as a colorless oil.

[0375] zwitterionic chelating agent 9

[0376]

[0377] In a typical experiment, alkyne 8 (4 equivalents), CuI (0.550 equivalents), and NaAsc (1.20 equivalents) were dissolved in degassed DMF / t-BuOH / H2O under a N2 atmosphere and stirred at room temperature for 30 min. Azide 7 (1.00 equivalents) was dissolved in degassed DMF / t-BuOH / H2O under a N2 atmosphere. The two solutions were combined and then stirred at 50 °C for 24 h. A solution of Na2S in water was then added to the mixture. The suspension was stirred at room temperature for 10 min, filtered, and the solvent was removed under vacuum. The crude product was dissolved in CH2Cl2 / TFA (1:1) and stirred for 4 h. The solvent was removed under vacuum, and the crude product was purified by crystallization to give title compound 9.

[0378] Example 2: Imaging of organisms

[0379] For in vivo characterization, 40 pmol / g (average 10 nmol) of zwitterionic metal chelating agent IV was injected into 25 g athymic nude mice carrying xenograft tumors. Simultaneous color video and positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance tomography (MRT) were acquired before injection, every second for the first 20 seconds, and every minute thereafter for 2 hours. Camera acquisition was kept constant (typically 100 ms) and selected to ensure all intensity measurements were within the linear range. Blood samples were taken via the tail vein at 0, 1, 2, 5, 10, 15, 30, 60, and 120 minutes. Intensity-time curves for all major organs and tissues could be quantified. Peak intensity and time for each tumor / tissue / organ, as well as the intensity at 1 hour post-injection, could be determined.

[0380] Other implementation plans

[0381] It should be understood that although the invention has been described in conjunction with its detailed description, the foregoing description is intended to be illustrative and not to limit the scope of the invention, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the appended claims.

[0382] Those skilled in the art will recognize or be able to determine many equivalent schemes of the specific embodiments of the invention described herein using only conventional experiments.

[0383] Such equivalents are intended to be covered in the appended claims.

[0384] References

[0385]

[0386]

[0387] All patents, patent applications and publications cited in this article are incorporated herein in their entirety by reference.

Claims

1. A zwitterionic metal chelating agent complex comprising a metal chelating agent having one or more zwitterionic groups and a metal or metal isotope selected from radionuclides, labeled, paramagnetic metals and heavy metals.

2. The zwitterionic metal chelating agent complex according to claim 1, wherein the metal chelating agent is a derivative of DOTA, deferoxamine, NOA, PyC3A, macropa, porphyrin, or DOTAM.

3. The zwitterionic metal chelating agent complex according to claim 1, further comprising one or more targeting carriers.

4. The zwitterionic metal chelating agent complex according to claim 3, wherein one or more targeting carriers are cRGD, KUE, PSMA-617, FAPI, octreotide, bufotoxin, or homodimers or heterodimers formed by combinations thereof.

5. The zwitterionic metal chelating agent complex according to claim 1, wherein the metal chelating agent is a derivative of DOTA, and the metal or metal isotope is Pb, Zr, Cu, Ga, In, Y, Gd, Lu, Ac, or Tb.

6. The zwitterionic metal chelating agent complex according to claim 1, wherein the metal chelating agent is PyC3A, and the metal or metal isotope is Mn.

7. The zwitterionic metal chelating agent complex according to claim 1, wherein the metal chelating agent is macropa, and the metal or metal isotope is Ac. 3+ Or Bi 3+ .

8. The zwitterionic metal chelating agent complex according to claim 1, wherein the metal chelating agent is a derivative of NOA, and the metal or metal isotope is Ga. 3+ Cu 2+ Gd 3+ Ac 3+ Or Bi 3+ .

9. The zwitterionic metal chelating agent complex according to claim 1, wherein the metal chelating agent is a derivative of iron-sensitive derivatives, and the metal or metal isotope is Zr. 4+ Fe 3+ Mn 2+ or Mn 3+ .

10. The zwitterionic metal chelating agent complex according to claim 1, wherein the metal chelating agent is a porphyrin derivative, and the metal or metal isotope is Mn. 2+ Mn 3+ Fe 2+ Fe 3+ Gd 3+ Ac 3+ Or Bi 3+ .

11. The zwitterionic metal chelating agent complex according to claim 2, wherein the zwitterionic metal chelating agent in the zwitterionic metal chelating agent complex has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group.

12. The zwitterionic metal chelating agent complex according to claim 2, wherein the zwitterionic metal chelating agent in the zwitterionic metal chelating agent complex has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group.

13. The zwitterionic metal chelating agent complex according to claim 2, wherein the zwitterionic metal chelating agent in the zwitterionic metal chelating agent complex has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group.

14. The zwitterionic metal chelating agent complex according to claim 2, wherein the zwitterionic metal chelating agent in the zwitterionic metal chelating agent complex has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group.

15. The zwitterionic metal chelating agent complex according to claim 2, wherein the zwitterionic metal chelating agent in the zwitterionic metal chelating agent complex has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group.

16. The zwitterionic metal chelating agent complex according to claim 2, wherein the zwitterionic metal chelating agent in the zwitterionic metal chelating agent complex has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group.

17. The zwitterionic metal chelating agent complex according to claim 2, wherein the metal chelating agent is a derivative of DOTAM, and the metal or metal isotope is Pd, Pb, Zr, Cu, Ga, In, Y, Gd, Lu, Ac, or Tb.

18. The zwitterionic metal chelating agent complex according to claim 17, wherein the zwitterionic metal chelating agent in the zwitterionic metal chelating agent complex has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, each instance of X represents a reactive group, and each instance of R represents hydrogen or alkyl.

19. A developer comprising the zwitterionic metal chelating agent complex according to claim 1.

20. A method for imaging cells, tissues, or organs, the method comprising: (a) Contacting the cells with the imaging agent according to claim 19; as well as (b) Image the cells, tissues or organs using positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI).

21. The method for imaging cells according to claim 20, wherein the cells are tumor cells or cells undergoing angiogenesis.

22. The method of imaging cells according to claim 20, wherein the imaging agent is applied to an organism containing or suspected of containing the cells.

23. The method for imaging cells according to claim 22, wherein the organism is a human being.

24. The method for imaging cells according to claim 20, wherein the tissue or cells are imaged in vivo.

25. A therapeutic agent comprising the zwitterionic metal chelating agent complex according to claim 1, and a pharmaceutically acceptable carrier or excipient.

26. A method for treating cancerous conditions in individuals with this need, the method comprising: Contact the cancer cells of the object with an effective amount of the therapeutic agent according to claim 25. The metal atoms that combine with the zwitterionic metal chelating agent are: A known radioactive metallic isotope emits ionizing radiation, which causes cell death upon ingestion of the analogue. Or non-radioactive metals that can release cytotoxic radiation after irradiation with alpha radiation, beta radiation, neutron capture, or a combination thereof.

27. The method of treating cancerous conditions in a subject with such need as claimed in claim 26, wherein the metal atom complexed with the zwitterionic metal chelator is a non-radioactive metal capable of releasing cytotoxic radiation after irradiation with alpha radiation, beta radiation, neutron capture, or a combination thereof; the method further comprising the step of irradiating tumor cells with alpha radiation, beta radiation, neutron capture, or a combination thereof.

28. The method of treating cancerous conditions in an object with such need as claimed in claim 26, wherein the cancer cells are adult solid tumor cells or pediatric solid tumor cells.

29. The method of treating cancerous conditions in an object with such need as claimed in claim 26, wherein the cancer cells are melanoma cells, neuroblastoma cells, lung cancer cells, adrenal cancer cells, colon cancer cells, colorectal cancer cells, ovarian cancer cells, prostate cancer cells, liver cancer cells, subcutaneous cancer cells, squamous cell carcinoma cells, colon cancer cells, retinoblastoma cells, cervical cancer cells, glioma cells, breast cancer cells, pancreatic cancer cells, Ewing sarcoma cells, rhabdomyosarcoma cells, osteosarcoma cells, retinoblastoma cells, nephroblastoma cells, and pediatric brain tumor cells.

30. The method of treating cancer in a subject with such need, according to claim 26, wherein the cancer cells are prostate cancer cells.

31. The method of treating cancerous conditions in an object with such need as claimed in claim 26, wherein the cancer cells are malignant cancer cells.

32. A method for treating non-cancerous conditions in individuals with this need, said method comprising: Apply an effective amount of the therapeutic agent according to claim 25 to the object. The metal atoms that combine with the zwitterionic metal chelating agent are: A known radioactive metallic isotope emits ionizing radiation, which results in a therapeutic effect on the object. Or a non-radioactive metal that can release therapeutic radiation after irradiation with alpha radiation, beta radiation, neutron capture, or a combination thereof.

33. The method of treating a noncancerous condition in an object with such need, as described in claim 32, wherein the noncancerous condition is a musculoskeletal disorder or a tissue hypertrophy disorder.

34. The method of treating a non-cancerous condition in a person in need, as described in claim 32, wherein the person is a human being.

35. A diagnostic agent comprising the zwitterionic metal chelating agent complex according to claim 1, and a pharmaceutically acceptable carrier or excipient.

36. A method for measuring the efficacy of a biological system of an object, the method comprising: (a) Administering a quantifiable amount of the diagnostic agent according to claim 35 to the subject; (b) Imaging the subject using positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); and (c) Determine the amount of therapeutic agent present in the biological system observed in the object.

37. The method for measuring the efficacy of a biological system of an object according to claim 36, wherein the biological system is a renal system, a hepatic system, or a blood pool.

38. A method for measuring the efficacy of renal function in a subject, the method comprising: (a) Administering a quantifiable amount of the diagnostic agent according to claim 35 to the subject; (b) Imaging the subject using positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI); and (c) Determine the amount of therapeutic agent present in the biological system observed in the object.

39. A method for quantifying the glomerular filtration rate of a subject, the method comprising: (a) Administering a quantifiable amount of the diagnostic agent according to claim 35 to the subject; (b) Using measurements of each bodily fluid or imaging the subject with positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI), determine the amount of diagnostic agent present in the subject's blood and urine as a function of time.

40. A method for removing toxic or excessive metals from an object requiring such treatment, the method comprising: (a) Applying a therapeutically effective amount of the therapeutic agent according to claim 25 to the subject, The therapeutic agent comprises a metal chelating agent having one or more zwitterionic groups not coordinated with a metal or metal isotope, and a pharmaceutically acceptable carrier or excipient.

41. The method for removing toxic or excessive metals from an object requiring such treatment, according to claim 40, wherein the metal chelating agent in the therapeutic agent has the following formula: Where ZWI represents zwitterionic groups; each instance of W and Y independently represents a linking group, and each instance of X represents a reactive group.

42. The method of removing toxic or excessive metals from an object requiring such treatment according to claim 40, wherein the toxic or excessive metal is lead, mercury, arsenic, cadmium, thallium, iron, zinc, chromium, manganese, aluminum, cobalt, selenium, beryllium, lithium, silver, or tin.

43. A radiosurgical method for treating a patient's body, the method comprising: Receive the desired lesion pattern and planned radiation distribution; Apply an effective amount of the diagnostic agent according to claim 35 to the subject to effectively image the desired lesion pattern; Surgery is performed on the desired lesion pattern to treat the patient's body.

44. The radiosurgery method according to claim 43, wherein the zwitterionic metal chelating agent of the diagnostic agent further comprises one or more targeting carriers. The one or more targeting vectors are cRGD, PSMA-617, FAPI, octreotide, bufotoxin, or homodimers or heterodimers formed by combinations thereof.

45. The radiosurgery method of claim 43, wherein the desired lesion pattern is received from the user interface of the treatment planning module.

46. ​​The radiosurgery method of claim 45, wherein the treatment planning module is pre-programmed with instructions for various disease states and cancerous conditions.

47. The radiosurgery method of claim 45, wherein the treatment planning module uses artificial intelligence data to identify lesion patterns for a variety of disease states and cancerous conditions.

48. The radiosurgery method of claim 43, wherein the surgery is performed using a stereotactic radiosurgery system.

49. A method of treating cancer by administering an effective amount of the therapeutic agent according to claim 25, wherein the method includes the steps of diagnosing the cancer and administering the therapeutic agent to a subject determined to have such a need; The steps involved in diagnosing the cancer include: To bring the subject's cells, tissues, or organs into contact with the imaging agent. The cells, tissues, or organs of the subject are imaged using positron emission tomography (PET), single-photon emission computed tomography (SPECT), or magnetic resonance imaging (MRI), and Diagnose the cancer in the cells, tissues or organs of the object based on the collected imaging data; Furthermore, the metal atoms that are complexed with the zwitterionic metal chelating agent are: A known radioactive metallic isotope emits ionizing radiation, which causes cell death upon ingestion of the analogue. Or non-radioactive metals that can release cytotoxic radiation after irradiation with alpha radiation, beta radiation, neutron capture, or a combination thereof.

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