Copper-containing theragnostic compounds and methods of using them

Abstract

The present technology provides compounds, and compositions comprising such compounds, useful for imaging and / or treating non-small cell lung cancer, small cell carcinoma of the lung, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumors, pituitary tumors, vasoactive intestinal peptide-secreting tumors, glioma, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and / or metastatic cancer. The compounds comprise a tumor targeting domain (comprising a moiety capable of recognizing or interacting with a molecular target on the surface of a tumor cell), a blood protein binding domain, and a sarcofadin-containing domain, wherein the portion of the tumor targeting domain is distal to and not sterically hindered by the blood protein binding domain.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 020,838, filed on May 6, 2020, whose entire disclosure is incorporated herein by reference for any and all purposes.

[0002] The present invention generally relates to a trifunctional structure comprising a tumor targeting domain (the tumor targeting domain includes a portion capable of recognizing or interacting with molecular targets on the surface of tumor cells), a blood protein binding domain, and a sarcofadin-containing domain, wherein the tumor targeting domain portion is distal to the blood protein binding domain and is not sterically hindered by the blood protein binding domain. The sarcofadin-containing domain of the compounds of the present invention is 64 Cu +2 or 67 Cu +2 It is possible to chelate them. The technology of the present invention also provides compositions containing such compounds and methods for their use in imaging and / or antitumor therapy. For example, the compounds and compositions of the technology of the present invention are useful theranostic compounds. [Background technology]

[0003] The theranostics concept describes using matched pairs of radionuclides to enable the quantification of radioactivity distribution within the body, followed by radioligand therapy using the same delivery vector. [Overview of the Initiative]

[0004] In one embodiment, a compound is provided comprising a tumor targeting domain (the tumor targeting domain includes a portion capable of recognizing or interacting with molecular targets on the surface of tumor cells), a blood protein binding domain, and a sarcofazine-containing domain, wherein the portion of the tumor targeting domain is distal to the blood protein binding domain and is not sterically hindered by the blood protein binding domain. The tumor targeting domain in the embodiments herein may be capable of binding to tumor-related molecular targets, including one or more of the following: tumor-related molecular targets that are tumor-specific cell surface proteins or other markers, e.g., prostate-specific membrane antigen (PSMA), somatostatin peptide receptor-2 (SSTR2), alpha v beta 3 (αvβ3), alpha v beta 6, gastrin-releasing peptide receptor, septase (e.g., fibroblast-activating protein alpha (FAP-alpha)), incretin receptor, glucose-dependent insulin-secreting Polypeptide receptors, VIP-1, NPY, folate receptors, LHRH, neuron transporters (e.g., norepinephrine transporter (NET)), EGFR, HER-2, VGFR, MUC-1, CEA, MUC-4, ED2, TF antigen, endothelial-specific markers, neuropeptide Y, uPAR, TAG-72, claudin, CCK analog, VIP, bombesin, VEGFR, tumor-specific cell surface proteins, GLP-1, CXCR4, hepsin, TMPRSS2, caspace, cMET, or overexpressed peptide receptors. The tumor targeting domain of any embodiment disclosed herein may include modified antibodies, modified antibody fragments, modified binding peptides, prostate-specific membrane antigen ("PSMA") binding peptides, somatostatin receptor agonists, bombesin receptor agonists, seplasin binding compounds, or any one or more binding fragments thereof.

[0005] In any embodiment of the technology of the present invention disclosed herein, the compound is any one of formulas I to V, or a pharmaceutically acceptable salt and / or solvate thereof. [ka] (wherein TTD is a tumor targeting domain of any of the embodiments disclosed herein, BBD is a blood protein binding domain of any of the embodiments disclosed herein, Sarc is a sarcophagazine-containing domain of any of the embodiments disclosed herein, X 1 is, independently at each occurrence, absent, O, S, NH, -C(O)-, -C(O)-NR 1 -, -NR 2 -, -C(O)-, -C(O)-NR 3 -C1-C 12 alkylene-, -C1-C 12 alkylene-C(O)-, -C(O)-NR 4 -C1-C 12 alkylene-C(O)-, -arylene-, -heterocycle-, -O(CH2CH2O) a -, -CH2CH2-O(CH2CH2O) b -, -CH2CH2-O(CH2CH2O) c -CH2CH2-, -O(CH2CH2O) d -CH2CH2-, -C(O)-O(CH2CH2O) e -, -O(CH2CH2O) f -CH2CH2C(O)-, -C(O)-O(CH2CH2O) g -, -C(O)-O(CH2CH2O) h -CH2CH2-, -C(O)-O(CH2CH2O) i -CH2CH2C(O)-, -CH2CH2-O(CH2CH2O) j -CH2CH2C(O)-, -C(O)-NR 5 -CH2CH2O(CH2CH2O) k -, -C(O)-NR 6 -CH2CH2O(CH2CH2O) l -CH2CH2-, -C(O)-NR 7 -CH2CH2O(CH2CH2O) m-CH2CH2C(O)-, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any combination of two or more thereof, where a, b, c, d, e, f, g, h, i, j, k, l, and m are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 in each occurrence, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In each occurrence, independently, it is H, alkyl, or aryl. L 1 In each occurrence, independently, the non-existent O, S, NH, -C(O)-, and -C(O)-NR exist. 8 -, -NR 9 -C(O)-, -C(O)-NR 10 -C1-C 12 Alkylene-,-C1-C 12 Alkylene-C(O)-,-C(O)-NR 11 -C1-C 12 Alkylene-C(O)-, -arylene-, -heterocyclene-, -O(CH2CH2O) a’ -,-CH2CH2-O(CH2CH2O) b’ -,-CH2CH2-O(CH2CH2O) c’ -CH2CH2-, -O(CH2CH2O) d’ -CH2CH2-, -C(O)-O(CH2CH2O) e’ -, -O(CH2CH2O) f’ -CH2CH2C(O)-、-C(O)-O(CH2CH2O) g’ -, -C(O)-O(CH2CH2O) h’ -CH2CH2-, -C(O)-O(CH2CH2O) i’ -CH2CH2C(O)-, -CH2CH2-O(CH2CH2O) j’ -CH2CH2C(O)-, -C(O)-NR 12 -CH2CH2O(CH2CH2O) k’ -, -C(O)-NR 13-CH2CH2O(CH2CH2O) l’ -CH2CH2-, -C(O)-NR 14 -CH2CH2O(CH2CH2O) m’ -CH2CH2C(O)-, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any combination of two or more thereof, where a', b', c', d', e', f', g', h', i', j', k', l', and m' are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 in each occurrence, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 In each occurrence, independently, it is H, alkyl, or aryl. L 2 In each occurrence, independently, the non-existent O, S, NH, -C(O)-, and -C(O)-NR exist. 15 -, -NR 16 -C(O)-, -C(O)-NR 17 -C1-C 12 Alkylene-,-C1-C 12 Alkylene-C(O)-,-C(O)-NR 18 -C1-C 12 Alkylene-C(O)-, -arylene-, -heterocyclene-, -O(CH2CH2O) a’’ -,-CH2CH2-O(CH2CH2O) b’’ -,-CH2CH2-O(CH2CH2O) c’’ -CH2CH2-, -O(CH2CH2O) d’’ -CH2CH2-, -C(O)-O(CH2CH2O) e’’ -, -O(CH2CH2O) f’’ -CH2CH2C(O)-、-C(O)-O(CH2CH2O) g’’ -, -C(O)-O(CH2CH2O) h’’ -CH2CH2-, -C(O)-O(CH2CH2O) i’’ -CH2CH2C(O)-, -CH2CH2-O(CH2CH2O) j’’-CH2CH2C(O)-, -C(O)-NR 19 -CH2CH2O(CH2CH2O) k’’ -, -C(O)-NR 20 -CH2CH2O(CH2CH2O) l’’ -CH2CH2-, -C(O)-NR 21 -CH2CH2O(CH2CH2O) m’’ -CH2CH2C(O)-, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any combination of two or more thereof, and a'', b'', c'', d'', e'', f'', g'', h'', i'', j'', k'', l'', and m'' are, independently at each occurrence, 0, 1, 2, 3, 4, �, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, and R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 are, independently at each occurrence, H, alkyl, or aryl, p is, independently at each occurrence, 0, 1, 2, 3, 4, or 5, q is, independently at each occurrence, 1 or 2)

[0006] In any of the embodiments of the compounds disclosed herein, the sarcophagine-containing domain may or may not chelate 64 Cu +2 or 67 Cu +2 . In one aspect, there is provided a composition comprising a compound of any of the embodiments disclosed herein and also comprising a pharmaceutically acceptable carrier.

[0007] In one embodiment, for imaging and / or detecting one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumor, pituitary tumor, vasoactive enteropeptide-secreting tumor, glioma, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer, 64 Cu +2 or 67 Cu +2 A pharmaceutical composition is provided comprising an effective amount of a compound of any embodiment disclosed herein that chelates and a pharmaceutically acceptable carrier. In related embodiments, for imaging and / or detecting cancer, 64 Cu +2 or 67 Cu +2 A method is provided which includes the steps of administering an effective amount of a compound of any embodiment disclosed herein that chelates a substance, and detecting, after administration, one or more of the following: positron emission, gamma rays from positron emission and annihilation, and Cherenkov rays from positron emission.

[0008] In one embodiment, for the treatment of one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancers, 64 Cu +2 or 67 Cu +2 A pharmaceutical composition is provided comprising an effective amount of a compound of any embodiment disclosed herein that chelates and a pharmaceutically acceptable carrier. In related embodiments, 64 Cu +2 or 67 Cu +2A method for treating cancer is provided, comprising the step of administering an effective amount of a compound of any embodiment disclosed herein that chelates the cancer. [Brief explanation of the drawing]

[0009] [Figure 1A] This figure shows the HPLC chromatograms of spike samples of the technology of the present invention according to the examples. Figure 1A is the HPLC chromatogram of the [64Cu]Cu-RPS-085 sample. The upper chromatogram is the UV absorbance at 280 nm, and the lower is the corresponding radiochromatogram. [Figure 1B] This figure shows the HPLC chromatogram of a spike sample of the technology of the present invention, as demonstrated in the examples. Figure 1B is the HPLC chromatogram of the [67Cu]Cu-RPS-085 sample. The upper chromatogram shows the UV absorbance at 280 nm, and the lower chromatogram shows the corresponding radiochromatogram. [Figure 2A] This figure shows the radioHPLC chromatogram of [67Cu]Cu-RPS-063 after 20 minutes at 25°C, according to the example. [Figure 2B] This figure shows the radioHPLC chromatogram of [67Cu]Cu-RPS-063 after purification by solid-phase extraction at 25°C for 20 minutes, according to the example. [Figure 3] This figure shows micro-PET / CT images of the [64Cu]Cu-RPS-085 distribution in male Balb / Cnu / nu mice carrying LNCaP xenograft tumors, as described in the example. [Figure 4] This graph shows the tissue biodistribution of f[64Cu]Cu-RPS-085 in male Balb / Cnu / nu mice holding LNCaP xenografts, as demonstrated in the example. [Figure 5] This graph shows the tissue biodistribution of [67Cu]Cu-RPS-085 in male Balb / Cnu / nu mice holding LNCaP xenografts, as demonstrated in the example. [Figure 6]This graph shows the time-activity curves of f[67Cu]Cu-RPS-085 and [177Lu]Lu-RPS-063 in LNCaP tumors and kidneys of male Balb / Cnu / nu mice, based on the examples. [Modes for carrying out the invention]

[0010] The following terms will be used throughout as defined below. Where used herein and in the appended claims, singular articles, such as "a," "an," and "the" and similar referents, shall be construed to encompass both singular and plural forms in the context describing the element (particularly in the context of the following claims), unless otherwise noted herein or the context more clearly contradicts it. The enumeration of ranges of values ​​herein is intended merely as a simple way to refer individually to each distinct value that falls within the range, unless otherwise noted herein, and each distinct value is incorporated into the specification as if it were individually listed herein. All methods described herein may be carried out in any suitable order, unless otherwise noted herein or the context more clearly contradicts it. Any and all embodiments provided herein, or the use of exemplary language (e.g., "such as"), are intended merely to better illustrate the embodiments and, unless otherwise stated, do not imply any limitation to the claims. No language in the specification should be construed as indicating any unclaimed element as an absolutely necessary element.

[0011] Where used herein, “approximately” is understood by those skilled in the art and varies to some extent depending on the context in which it is used. Where there is a use of a term that is not obvious to those skilled in the art, given the context in which it is used, “approximately” means up to plus or minus 10% of the given term. For example, “approximately 10% by mass” is understood to mean “9% to 11% by mass.” When “approximately” precedes a term, it should be understood that the term is interpreted as disclosing both the term that is “approximately” and the term without the modification by “approximately.” For example, “approximately 10% by mass” discloses “9% to 11% by mass” and “10% by mass.”

[0012] When used in this disclosure, the phrase "and / or" is understood to mean any one of the individually listed members or any combination of two or more of them. For example, "A, B, and / or C" means "A, B, C, A and B, A and C, or B and C."

[0013] As used herein, the term “amino acid” includes naturally occurring α-amino acids and synthetic α-amino acids (e.g., 2-amino-2-phenylacetic acid, also known as phenylglycine), as well as α-amino acid analogs and amino acid mimetic compounds that function in a manner similar to naturally occurring amino acids. Unless otherwise specified, the term further includes both L and D forms of such α-amino acids. Naturally occurring amino acids are those encoded by the genetic code, as well as later modified amino acids, such as hydroxyproline, γ-carboxyglutamate, and O-phosphoserine. Amino acid analogs refer to compounds that have the same basic chemical structure as naturally occurring amino acids, e.g., α-carbon-holding organic groups, e.g., homoserine, norleucine, methionine sulfoxide, methionine methylsulfonium. Such analogs may have modified organic groups (e.g., norleucine) or modified peptide skeletons, but may retain the same basic chemical structure as naturally occurring amino acids. Amino acid mimetic compounds refer to chemical compounds that have a different structure from the general chemical structure of amino acids, but function in a manner similar to naturally occurring amino acids. Amino acids may be referred to herein by either these commonly known three-letter symbols or the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.

[0014] As used herein, the terms “polypeptide,” “peptide,” and “protein” are interchangeable herein and mean polymers containing two or more amino acids linked to each other by peptide bonds or modified peptide bonds, i.e., peptide counterparts. Polypeptides refer to both short chains, commonly called peptides, glycopeptides, or oligomers, and long chains, commonly called proteins. Polypeptides may contain amino acids other than the 20 genetically encoded amino acids. Polypeptides include amino acid sequences modified by natural processes, e.g., post-translational processing, or by chemical modification techniques well known in the art, as well as synthetic amino acids.

[0015] Generally, a reference to a particular element, such as hydrogen or H, is intended to include all isotopes of that element. For example, if the R group is defined as containing hydrogen or H, this also includes deuterium and tritium. Thus, radioactive isotopes, such as tritium and C, are included. 14 , P 32 and S 35 Compounds containing the label are within the scope of the present invention. Procedures for inserting such labels into compounds of the present invention will be readily apparent to those skilled in the art based on the disclosure herein. Generally, "substituted" refers to an organic group (e.g., an alkyl group) as defined below, in which one or more bonds to hydrogen atoms within it are replaced by bonds to non-hydrogen or non-carbon atoms. A substituted group also includes a group in which one or more bonds to carbon(or hydrogen) atoms are replaced by one or more bonds to heteroatoms, including double or triple bonds. Thus, unless otherwise specified, a substituted group is substituted with one or more substituents. In some embodiments, a substituted group is substituted with one, two, three, four, five, or six substituents. Examples of substituents, but not limited to these, include: halogens (i.e., F, Cl, Br, and I); hydroxyl; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyl (oxo); carboxylate; ester; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; thiol; sulfide; sulfoxide; sulfone; sulfonyl; pentafluorosulfanil (i.e., SF5), sulfonamide; amine; N-oxide; hydrazine; hydrazide; hydrazone; azide; amide; urea; amidine; guanidine; enamine; imide; isocyanate; isothiocyanate; cyanic acid; thiocyanate; imine; nitro group; and nitrile (i.e., CN).

[0016] Substituted cyclic groups, such as substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl groups, also include rings and ring systems in which bonds to hydrogen atoms are replaced by bonds to carbon atoms. Therefore, substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below. When used in this specification, C m -C n For example, C1-C 12 When used before a group, C1-C8 or C1-C6 refers to a group containing m to n carbon atoms.

[0017] Alkyl groups include linear and branched alkyl groups having 1 to 12 carbon atoms, typically 1 to 10 carbon atoms, or, in some embodiments, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Examples of linear alkyl groups include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups, but not limited to these, include isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Alkyl groups may be substituted or unsubstituted. Typical substituted alkyl groups may be substituted once or more times with substituents, such as those listed above, and are not limited to haloalkyls (e.g., trifluoromethyl), hydroxyalkyls, thioalkyls, aminoalkyls, alkylaminoalkyls, dialkylaminoalkyls, alkoxyalkyls, and carboxyalkyls.

[0018] Examples of cycloalkyl groups include monocyclic, bicyclic, or tricyclic alkyl groups having 3 to 12 carbon atoms in the ring(s), or in some embodiments, 3 to 10, 3 to 8, 3 to 4, 5, or 6 carbon atoms. Exemplary monocyclic cycloalkyl groups, but not limited to these, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Examples of bicyclic and tricyclic rings include both cross-linked cycloalkyl groups and fused rings, such as, but not limited to, bicyclo[2.1.1]hexane, adamantyl, and dekalinyl. Cycloalkyl groups may be substituted or unsubstituted. Substituted cycloalkyl groups may be substituted once or multiple times with non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings substituted with linear or branched alkyl groups as defined above. Typical substituted cycloalkyl groups may be monosubstituted or more than once, and may include, for example, 2,2-, 2,3-, 2,4-, 2,5-, or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents listed above.

[0019] A cycloalkylalkyl group is an alkyl group as defined above, wherein the hydrogen or carbon bonds of the alkyl group are replaced by bonds to a cycloalkyl group as defined above. In some embodiments, a cycloalkylalkyl group has 4 to 16 carbon atoms, 4 to 12 carbon atoms, and usually 4 to 10 carbon atoms. Cycloalkylalkyl groups may be substituted or unsubstituted. A substituted cycloalkylalkyl group may be substituted in the alkyl moiety of the group, in the cycloalkyl moiety, or in the alkyl and cycloalkyl moiety. Typical substituted cycloalkylalkyl groups may be monosubstituted or more than once, and may be monosubstituted, disubstituted, or trisubstituted with substituents, such as those listed above, for example.

[0020] Alkenyl groups include linear and branched alkyl groups as defined above, except that they have at least one double bond between two carbon atoms. Alkenyl groups have 2 to 12 carbon atoms, usually 2 to 10 carbon atoms, or in some embodiments, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, alkenyl groups have one, two, or three carbon-carbon double bonds. Examples, but not limited to, include vinyl, aryl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), and -C(CH2CH3)=CH2. Alkenyl groups may be substituted or unsubstituted. Typical substituted alkenyl groups may be monosubstituted or more than once, and may be monosubstituted, disubstituted, or trisubstituted with substituents, such as those listed above, for example, but not limited to these.

[0021] Examples of cycloalkenyl groups include cycloalkyl groups, as defined above, having at least one double bond between two carbon atoms. Cycloalkenyl groups may be substituted or unsubstituted. In some embodiments, cycloalkenyl groups may have one, two, or three double bonds, but do not include aromatic compounds. Cycloalkenyl groups have 4 to 14 carbon atoms, or in some embodiments, 5 to 14 carbon atoms, 5 to 10 carbon atoms, or further 5, 6, 7, or 8 carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, cyclobutadienyl, and cyclopentadienyl. A cycloalkenylalkyl group is an alkyl group as defined above, wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond to a cycloalkenyl group as defined above. Cycloalkenylalkyl groups may be substituted or unsubstituted. A substituted cycloalkenylalkyl group may be substituted in the alkyl moiety, in the cycloalkenyl moiety, or in both the alkyl and cycloalkenyl moieties. Typical substituted cycloalkenylalkyl groups may be substituted once or more times with substituents, such as those listed above.

[0022] Alkynyl groups include linear and branched alkyl groups as defined above, except that they have at least one triple bond between two carbon atoms. Alkynyl groups have 2 to 12 carbon atoms, typically 2 to 10 carbon atoms, or in some embodiments, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, alkynyl groups have one, two, or three carbon-carbon triple bonds. Examples, but not limited to these, include -C≡CH, -C≡CCH3, -CH2C≡CCH3, and -C≡CCH2CH(CH2CH3)2. Alkynyl groups may be substituted or unsubstituted. Typical substituted alkynyl groups may be monosubstituted or more than once, and may be monosubstituted, disubstituted, or trisubstituted with substituents, such as those listed above, for example, but not limited to these.

[0023] An aryl group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. The aryl groups used herein include monocyclic, bicyclic, and tricyclic ring systems. Therefore, examples of aryl groups, though not limited to these, include phenyl, azlenyl, heptarenyl, biphenyl, fluorenyl, phenantrenyl, anthracenyl, indenyl, indanyl, pentarenyl, and naphthyl groups. In some embodiments, the aryl group contains 6 to 14 carbon atoms in the ring portion of the group, and in other embodiments, it contains 6 to 12 or even 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. The aryl group may be substituted or unsubstituted. The phrase "aryl group" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). Typical substituted aryl groups may be monosubstituted or more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents, such as those listed above.

[0024] An aralkyl group is an alkyl group as defined above, in which the hydrogen or carbon bonds of the alkyl group are replaced by bonds to an aryl group as defined above. In some embodiments, the aralkyl group contains 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. The aralkyl group may be substituted or unsubstituted. A substituted aralkyl group may be substituted in the alkyl portion of the group, in the aryl portion, or in both the alkyl and aryl portions. Representative aralkyl groups, but not limited to these, include benzyl and phenethyl groups and condensed (cycloalkylaryl)alkyl groups, such as 4-indanylethyl. Representative substituted aralkyl groups may be substituted once or more times with substituents, such as those listed above.

[0025] Heterocyclyl groups include aromatic (also called heteroaryl) and non-aromatic ring compounds, of which one or more are heteroatoms, for example, but not limited to, N, O, and S, comprising three or more ring members. In some embodiments, heterocyclyl groups contain one, two, three, or four heteroatoms. In some embodiments, heterocyclyl groups include monocyclic, bicyclic, and tricyclic rings having 3 to 16 ring members, while other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. Heterocyclyl groups include aromatic, partially unsaturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl groups. The phrase “heterocyclyl group” includes fused ring species, such as those containing condensed aromatic and non-aromatic groups, for example, benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxynyl, and benzo[1,3]dioxolyl. This phrase also includes bridged polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyls. The heterocyclyl group may be substituted or unsubstituted.As heterocyclyl groups, there are, but are not limited to, azilidinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranil, dioxolyl, furanil, thiophenyl, pyrrolyl, pyrrolinil, imidazolyl, imidazolinil, pyrazolyl, pyrazolinil, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinil, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, Piperazinyl, Morpholinyl, Thiomorpholinyl, Tetrahydropyranyl, Tetrahydrothiopyranyl, Oxatian, Dioxyl, Dithianyl, Pyranyl, Pyridyl, Pyrimidinyl, Pyridazinyl, Pyrazinyl, Triazinyl, Dihydropyridyl, Dihydrodithinyl, Dihydrodithionyl, Homopiperazinyl, Quinuclidyl, Indolyl, Indolinyl, Isoindolyl, Azaindolyl (Pyrrolopyridyl), Indazolyl, Indolidinyl, Benzotriazolyl, Benzimidazolyl, Benzofura Nyl, benzothiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxadinyl, benzodithinyl, benzoxathinyl, benzothiadinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolidinyl, quinoxalinyl, quinazolo Examples include linyl, synnolinyl, phthalazinyl, naphthilidinyl, pteridinyl, thianaphthyl, dihydrobenzothiadinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxynyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Typical substituted heterocyclyl groups may be monosubstituted or more than once, and may be, for example, 2-, 3-, 4-, 5-, or 6-substituted pyridyl or morpholinyl groups, or may be disubstituted with various substituents, such as those listed above.

[0026] A heteroaryl group is an aromatic ring compound containing five or more ring members, one or more of which are heteroatoms, for example, but not limited to N, O, and S. Examples of heteroaryl groups, though not limited to these, include pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanil, benzofuranil, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianafthyl, prinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups include fused ring compounds in which all rings are aromatic, such as those containing an indolyl group, and fused ring compounds in which only one of the rings is aromatic, such as the 2,3-dihydroindolyl group. Heteroaryl groups may be substituted or unsubstituted. Therefore, the phrase "heteroaryl group" includes fused ring compounds and heteroaryl groups having other groups bonded to one of the ring members, such as alkyl groups. Typical substituted heteroaryl groups may be substituted once or multiple times with various substituents, such as those listed above.

[0027] A heterocyclylalkyl group is an alkyl group as defined above, in which a hydrogen or carbon bond of the alkyl group is replaced by a bond to a heterocyclyl group as defined above. Heterocyclylalkyl groups may be substituted or unsubstituted. A substituted heterocyclylalkyl group may be substituted in the alkyl portion of the group, in the heterocyclyl portion, or in both the alkyl and heterocyclyl portions. Representative heterocyclylalkyl groups, but not limited to these, include morpholine-4-ylethyl, furan-2-ylmethyl, imidazole-4-ylmethyl, pyridine-3-ylmethyl, tetrahydrofuran-2-ylethyl, and indole-2-ylpropyl. Representative substituted heterocyclylalkyl groups may be substituted once or more times with substituents, such as those listed above.

[0028] A heteroaralkyl group is an alkyl group as defined above, in which the hydrogen or carbon bond of the alkyl group is replaced by a bond to a heteroaryl group as defined above. Heteroaralkyl groups may be substituted or unsubstituted. A substituted heteroaralkyl group may be substituted in the alkyl moiety, in the heteroaryl moiety, or in both the alkyl and heteroaryl moieties. Typical substituted heteroaralkyl groups may be substituted once or more times with substituents, such as those listed above. Groups described herein that have two or more bonding sites (i.e., divalent, trivalent, or polyvalent) in the compounds of the art of the present invention are designated by the use of the suffix "ene". For example, a divalent alkyl group is an alkylene group, a divalent aryl group is an arylene group, a divalent heterocyclyl group is a heterocyclene group, a divalent heteroaryl group is a heteroarylene group, and so on. Substituents having a single bonding site in the compounds of the art of the present invention are not referred to using the naming "ene". For example, chloroethyl is not referred to as chloroethylene herein. Such groups may be further substituted or unsubstituted.

[0029] An alkoxy group is a hydroxyl group (-OH) in which the bond to the hydrogen atom is replaced by a bond to the carbon atom of a substituted or unsubstituted alkyl group as defined above. Examples of linear alkoxy groups, but not limited to these, include methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy. Examples of branched alkoxy groups, but not limited to these, include isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy. Examples of cycloalkoxy groups, but not limited to these, include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy groups may be substituted or unsubstituted. Typical substituted alkoxy groups may be substituted once or multiple times with substituents, such as those listed above.

[0030] As used herein, the terms "alkanoyl" and "alkanoyloxy" may refer to -C(O)-alkyl and -OC(O)-alkyl groups, respectively, and in some embodiments, the alkanoyl or alkanoyloxy group contains 2 to 5 carbon atoms. Similarly, the terms "aryloyl" and "aryloyloxy" may refer to -C(O)-aryl and -OC(O)-aryl groups, respectively. The terms "aryloxy" and "arylalkoxy" refer to a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to an oxygen atom in an alkyl group, respectively. Examples, though not limited to these, include phenoxy, naphthyloxy, and benzyloxy. Typical substituted aryloxy and arylalkoxy groups may be substituted once or multiple times with substituents, such as those listed above.

[0031] The term "carboxylic acid" as used herein refers to a compound having a -C(O)OH group. The term "carboxylate" as used herein refers to a compound having a -C(O)OH group. -This refers to the group. "Protected carboxylate" refers to -C(O)OG (wherein G is the carboxylate protecting group). Carboxylate protecting groups are well known to those skilled in the art. A large list of protecting groups for carboxyl functional groups can be found in Protective Groups in Organic Synthesis, Greene, TW; Wuts, PGM, John Wiley & Sons, New York, NY, (3rd Edition, 1999), which is incorporated herein by reference in its entirety for any and all purposes as if fully described herein, and these protecting groups can be added or removed using the procedures described in that document. The term "ester" as used herein is -COOR 70 It refers to the base. R 70 These are substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl groups, as defined herein.

[0032] The term "amide" (or "amide") refers to C- and N-amide groups, i.e., -C(O)NR 71 R 72 , and -NR 71 C(O)R 72 Each contains a base. 71 and R 72 This is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group, as defined herein. Therefore, examples of amide groups, but not limited to these, include carbamoyl (-C(O)NH2) and formamide (-NHC(O)H). In some embodiments, the amide is -NR 71 C(O)-(C 1-5 In other embodiments, the amide is -NHC(O)-alkyl, and this group is called "carbonylamino". The terms "nitrile" or "cyano" as used herein refer to the -CN group.

[0033] The urethane group is an N- and O-urethane group, i.e., -NR 73 C(O)OR 74 and -OC(O)NR 73 R 74 Each contains a base. 73 and R 74 R is independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group, as defined herein. 73 H is also acceptable. The term "amine" (or "amino") is used herein by -NR 75 R 76 group (in the formula, R 75 and R 76 is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group (as defined herein). In some embodiments, the amine is an alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[0034] The term "sulfonamide" refers to S- and N-sulfonamide groups, i.e., -SO2NR 78 R 79 and -NR 78 SO2R 79 Each contains a base. 78 and R 79This group is independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group, as defined herein. Therefore, examples of sulfonamide groups, but not limited to these, include sulfamoyl (-SO2NH2) groups. In some embodiments herein, the sulfonamide is -NHSO2-alkyl and is referred to as an "alkylsulfonylamino" group.

[0035] The term "thiol" refers to the -SH group, while sulfides are -SR. 80 It contains the group, and the sulfoxide is -S(O)R 81 It contains the group, and the sulfone is -SO2R 82 It contains a group, and the sulfonyl group is -SO2OR 83 Includes R 80 , R 81 , R 82 , and R 83 Each of these is independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclyl, or heterocyclylalkyl group, as defined herein. In some embodiments, the sulfide is an alkylthio group or an -S-alkyl group. The term "urea" is -NR 84 -C(O)-NR 85 R 86 It refers to the base. R 84 , R 85 , and R 86 The groups are independently hydrogen, or substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl groups, as defined herein.

[0036] The term "amidine" is -C(NR 87 )NR 88 R 89 and -NR 87 C(NR 88 )R 89 It refers to R 87 , R88 , and R 89 Each of these is independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclyl, or heterocyclylalkyl group, as defined herein. The term "guanidine" is -NR 90 C(NR 91 )NR 92 R 93 (In the formula, R 90 , R 91 , R 92 and R 93 Each of these terms independently refers to hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylaralkyl, heterocyclyl, or heterocyclylalkyl group (as defined herein).

[0037] The term "enamin" is -C(R 94 )=C(R 95 )NR 96 R 97 and -NR 94 C(R 95 )=C(R 96 )R 97 (In the formula, R 94 , R 95 , R 96 and R 97 Each of these independently refers to hydrogen, a substituted or unsubstituted alkyl, a cycloalkyl, an alkenyl, an alkynyl, an arylaralkyl, a heterocyclyl, or a heterocyclylalkyl group (as defined herein). The terms "halogen" or "halo" as used herein refer to bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine. When used herein, the term "hydroxyl" refers to -OH or its ionized form -O - It can refer to... The term "imide" is -C(O)NR 98C(O)R 99 (wherein, R 98 and R 99 are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group, as defined herein). The term "imine" refers to -CR 100 (NR 101 ) and -N(CR 100 R 101 ) groups (wherein, R 100 and R 101 are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, arylalkyl, heterocyclyl or heterocyclylalkyl group, as defined herein, provided that R 100 and R 101 are not both hydrogen simultaneously).

[0038] The term "nitro" as used herein refers to the -NO2 group. The term "trifluoromethyl" as used herein refers to -CF3. The term "trifluoromethoxy" as used herein refers to -OCF3. The term "azide" refers to -N3. The term "trialkylammonium" refers to the -N(alkyl)3 group. The trialkylammonium group is positively charged and thus usually has an associated anion, such as a halogen anion.

[0039] The term "trifluoromethyldiaziridine" refers to

Chemical formula

[0040] As those skilled in the art will understand, for any and all purposes, and especially in terms of providing written explanations, all scopes disclosed herein also encompass any and all possible subranges and combinations thereof. Every scope enumerated is intended to fully describe how the same scope can be subdivided into at least two, three, four, five, ten, and so on, and how such subdivisions are possible is readily apparent. As a non-restrictive example, each scope discussed herein can easily be subdivided into a lower third, a middle third, an upper third, and so on. As similarly understood by those skilled in the art, all language, e.g., “up to,” “at least,” “greater than,” “less than,” etc., includes the enumerated number and refers to a scope that can subsequently be subdivided into subranges as discussed above. Finally, as understood by those skilled in the art, each scope includes its individual members. Thus, for example, a group having 1 to 3 atoms refers to a group having 1, 2, or 3 atoms. Similarly, groups having 1 to 5 atoms refer to groups having 1, 2, 3, 4, or 5 atoms, and so on.

[0041] pharmaceutically acceptable salts of the compounds described herein are within the scope of the art of the present invention and include acid addition salts or base addition salts that retain the desired pharmacological activity and are not biologically unsuitable (e.g., the salts are not excessively toxic, allergenic, or irritating, and are biologically usable). If the compounds of the art of the present invention have a basic group, for example, an amino group, the pharmaceutically acceptable salts can be formed with inorganic acids (e.g., hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginic acid, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (e.g., aspartic acid and glutamic acid). If the compounds of the art of the present invention have an acidic group, for example, a carboxylic acid group, the compounds can be formed with metals, for example, alkalis and earth alkali metals (e.g., Na + Li + , K + Ca 2+ Mg 2+ Zn 2+ ), ammonia, or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine, and ornithine) can form salts. Such salts can be prepared in situ during the isolation and purification of the compound, or by separately reacting the purified compound, in its free base or free acid form, with a suitable acid or base, and then isolating the salts thus formed.

[0042] Those skilled in the art will recognize that the compounds of the technology of the present invention may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and / or stereoisomerism. Since the diagrams of the formulas within the specification and claims can only represent one of the possible tautomeric, conformational, stereochemical or geometric isomeric forms, it should be understood that the technology of the present invention encompasses all tautomeric, conformational, stereochemical and / or geometric isomeric forms of the compounds having one or more of the utilities described herein, as well as mixtures of these various different forms. "Tautomers" refer to the isomeric forms of a compound that are in equilibrium with each other. The existence and concentration of the isomeric forms depend on the environment in which the compound is found and can vary, for example, depending on whether the compound is in the solid state or in an organic or aqueous solution. For example, in an aqueous solution, quinazolinone can exhibit the following isomeric forms, which are also called tautomers of each other:

[0043] <�

Chemical formula

[0044]

Chemical formula

[0045] The compounds of the present invention may exist as solvates, particularly hydrates. Hydrates may be formed during the manufacture of the compound or a composition containing the compound, or they may be formed over time due to the hygroscopic nature of the compound. The compounds of the present invention may also exist as organic solvent hydrates, including DMF, ethers, and alcohol solvates. Identification and preparation of any particular solvate is within the scope of the skills of those skilled in the art in the field of synthetic organic or medicinal chemistry. Throughout this disclosure, various publications, patents, and published patent specifications are referenced by identifying citations. Arabic numerals referring to these referenced citations are also within the scope of this disclosure, and complete bibliographic details of these are provided in the sections within the Examples. These publications, patents, and published patent specifications are incorporated herein by reference to more fully describe the art of the present invention.

[0046] The technology of the present invention Radioligands targeting prostate-specific membrane antigen (PSMA) have shown promising efficacy in the clinical imaging and therapy of prostate cancer. While antibody-targeted PSMA was the first ligand to undergo clinical evaluation, radiolabeled PSMA small molecule inhibitors have recently gained momentum due to their rapid accumulation in these tumors, clearance from non-target tissues, and a side effect profile considered to be fairly tolerable to patients. Many of these compounds utilize glutamate-urea-lysine or glutamate-urea-glutamate moieties to achieve PSMA targeting and high-affinity binding to PSMA. Among the PSMA-targeting ligands currently under clinical investigation are certain fluorine-18 or gallium-68-labeled diagnostic compounds for positron emission tomography (PET) tumor imaging, or iodine-131, lutetium-177, bismuth-213, or actinium-225-labeled therapeutic compounds for use in radioligand therapy targeting PSMA-expressing cancers.

[0047] The tissue distribution and clearance of small molecules are usually rapid, but copper-64 has a longer half-life (t 1 / 2 =12.7 hours) is Gallium-68(t 1 / 2 =68 minutes) or fluorine-18(t 1 / 2 This offers pharmacokinetic and delivery advantages over a longer half-life (109 minutes), including the possibility of distributing radioactive ligands from centralized production facilities. The longer half-life allows for long-term imaging, which can facilitate the detection of small metastatic lesions in areas with relatively high background. Although the probability of decay due to positron emission of copper-64 is lower (17.9%) compared to other radioactive metals, e.g., gallium-68 (89%), the emitted β + The low energy of copper-64 enables high-resolution PET imaging. Furthermore, copper-64 also has β - It decays upon release (39.0%), facilitating its potential application in radioligand therapy. In this context, copper-64 itself is a theranostic radioisotope.

[0048] The theranostics concept describes using matched pairs of radionuclides to enable quantification of radioactivity distribution within the body, followed by radioligand therapy using the same delivery vector, targeting PSMA. 177 In clinical targeted radioligand therapy using Lu-targeted ligands, indium-111 is typically used as a matched pair to lutetium-177 for initial dosimetry experiments. This strategy is possible because DOTA macrocyclic molecules can stably chelate many trivalent radioactive metals to such compounds. This means that the chemical structure of the delivery vector should, in principle, remain largely the same. However, the ligand's affinity for its target protein can change as the metal forming the complex changes. This alters its tissue distribution and potentially complicates dosimetry and pharmacokinetic model predictions.

[0049] Copper-64(t 1 / 2 = 12.7 hours, β + =17.9%, β - =39.0%) and copper-67(t 1 / 2 =2.58 days, β - Copper-67 (=100%) forms an interesting theranostic pair. Copper-67 exhibits a close agreement between its biological half-life and physical half-life when conjugated to many delivery vectors, its decay to non-toxic daughters, and its released β - Based on the tissue range of the particles (which is about a few cells in diameter within the tissue), it is a promising isotope for targeted radioligand therapy. 67 Cu-labeled radioligands target the same receptor in preclinical models. 177It has shown efficacy comparable to Lu-labeled radioligands. This theranostic radionuclide is once again attracting interest due to newly emerging methods for generating suitable radioactivity of copper-67, which has high specific activity. Matched pairs of copper-64 and copper-67 have been suggested to be advantageous for predictive dosimetry in targeted radioligand therapy, exhibiting a radiosafety profile comparable to currently used theranostic pairs. The intriguing properties of Cu-64 / Cu-67 are: 64 This stimulated the application of Cu-labeled PSMA-617 to prostate cancer imaging. Despite the good targeting of metastatic lesions, [ 64 The hepatic uptake of radioactivity after administration of Cu]Cu-PSMA-617 suggests suboptimal in vivo stability, limiting the potential application of such DOTA-conjugate ligands. There remains a need in the art for better compounds that target cancer antigens and provide theragnotics in cancer treatment and diagnosis. Since absorbed radiation dose is a function of the integral of cumulative radioactivity, there is a need for radiotherapy compounds that accumulate to a greater extent within tumors without causing unacceptable uptake in normal organs.

[0050] The technology of the present invention provides novel compounds that overcome these problems, and in particular, provides trifunctional compounds having multiple domains, including one domain that targets and binds to tumor markers with relatively high affinity, and another domain that binds to blood proteins, such as serum albumin, with moderate to weak affinity. These compounds include a chelate moiety with high selectivity for copper, and specifically are derivatives of 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosan, known as sarcofadin.

[0051] Therefore, in one embodiment, a compound is provided comprising a tumor targeting domain (the tumor targeting domain includes a portion capable of recognizing or interacting with molecular targets on the surface of tumor cells), a blood protein binding domain, and a sarcofazine-containing domain, wherein the tumor targeting domain is distal to the blood protein binding domain and is not sterically hindered by the blood protein binding domain.

[0052] As discussed above, the tumor targeting domain ("TTD") includes a portion capable of recognizing or interacting with molecular targets on the surface of tumor cells. Such molecular targets include cell surface proteins, e.g., receptors, enzymes, and antigens. For example, the molecular target may be a receptor, enzyme, and / or antigen expressed on the surface of tumor cells (e.g., tumor-specific cell surface proteins) capable of interacting with the tumor targeting domain. An example of such a tumor targeting domain is the glutamate-urea-lysine motif, recognized by the prostate-specific membrane antigen (PSMA), which is expressed on the surface of most prostate cancer cells. Another example is edotreotide, recognized by the somatostatin receptor, which is expressed on the surface of many neuroendocrine cancers. Therefore, the tumor targeting domains of any aspect and embodiment of this specification may be capable of binding to tumor-related molecular targets including one or more of the following: tumor-specific cell surface proteins or other markers, such as prostate-specific membrane antigen (PSMA), somatostatin peptide receptor-2 (SSTR2), alpha-v-beta 3 (αvβ3), alpha-v-beta 6, gastrin-releasing peptide receptor, seplase (e.g., fibroblast-activating protein alpha (FAP-alpha)), incretin receptor, glucose-dependent The targets include encephalin-secreting polypeptide receptors, VIP-1, NPY, folate receptors, LHRH, neuron transporters (e.g., norepinephrine transporter (NET)), EGFR, HER-2, VGFR, MUC-1, CEA, MUC-4, ED2, TF antigen, endothelial-specific markers, neuropeptide Y, uPAR, TAG-72, claudin, CCK analogs, VIP, bombesin, VEGFR, tumor-specific cell surface proteins, GLP-1, CXCR4, hepsin, TMPRSS2, caspace, cMET, or overexpressed peptide receptors. The aforementioned targets are merely representative tumor-related molecular targets, and detailed structural information for both the targets and the compounds that bind to them exists. Various antibodies, peptides, and compounds exhibiting specific affinity for these particular cellular targets are widely described in the scientific literature and can be adapted to the technology of the present invention as tumor targeting domains.The tumor targeting domains of any aspect and embodiment of this specification have at least moderate to high affinity (e.g., about 10). -8 M ~ about 10 -10 Equilibrium coupling constant (K) in the range of M D )) and it is possible to bind to tumor-related molecular targets.

[0053] Therefore, examples of tumor targeting domains include a portion that targets and binds to the active site of PSMA, and this includes, for example, glutamate-urea-amino acid sequences, glutamate-urea-lysine sequences with or without aromatic substituents in the epsilonamine of lysine, or any derivative thereof that can bind to the active site of PSMA with moderate to high affinity. Exemplary structures are provided herein, but other regions of PSMA may also be targeted, and these are interchangeable with the PSMA tumor targeting domains of the compounds detailed herein. One exemplary copper-containing trifunctional compound having affinity for PSMA is as follows:

[0054] [ka] (In the formula, "Cu" is 64 Cu +2 or 67 Cu +2 (It is fine.)

[0055] Seplase (or fibroblast-activating protein (FAP)) is an intrinsic membrane serine peptidase. In addition to its gelatinase activity, seplase has a dual function in tumor progression. Seplase promotes cellular invasion toward the extracellular matrix (ECM) and supports tumor growth and proliferation. As discussed above, tumor targeting domains may include a portion that binds to seplase, such as a seplase inhibitor. Exemplary structures of copper-containing trifunctional compounds that have affinity for FAP and are useful in the diagnosis and therapy of most cancers are shown below.

[0056] [ka] (In the formula, "Cu" is 64 Cu +2 or 67 Cu +2 (It's okay if it is)

[0057] Somatostatin is a peptide hormone that modulates the endocrine system and influences neurotransmission and cell proliferation through interaction with G protein-coupled somatostatin receptors and inhibition of the release of many secondary hormones. Somatostatin has two active forms, produced by the selective cleavage of a single preproprotein. There are five known somatostatin receptors, all of which are G protein-coupled transmembrane receptors: SST1 (SSTR1); SST2 (SSTR2); SST3 (SSTR3); SST4 (SSTR4); and SST5 (SSTR5). Exemplary somatostatin receptor agonists include somatostatin itself, lanreotide, octreotate, pasireotide, and bapreotide. Many neuroendocrine tumors express SSTR2 and other somatostatin receptors. Long-acting somatostatin agonists (e.g., octreotide, lanreotide) are used to stimulate the SSTR2 receptor and thus inhibit further tumor growth. See Zatelli MC, et al., (Apr 2007). “Control of pituitary adenoma cell proliferation by somatostatin analogs, dopamine agonists and novel chimeric compounds”. European Journal of Endocrinology / European Federation of Endocrine Societies.156 Suppl1:S29-35. Octreotide is an octapeptide that mimics natural somatostatin but has a significantly longer half-life in vivo. Octreotide is used to treat diarrhea in people with growth hormone-producing tumors (acromegaly and gigantism), pituitary tumors that secrete thyroid-stimulating hormone (thyrotropinoma), diarrhea and flushing symptoms associated with carcinoid syndrome, and vasoactive enteropeptide-secreting tumors (vipomas) when surgery is contraindicated. Lanreotide is used to treat acromegaly and symptoms caused by neuroendocrine tumors (mostly carcinoid syndrome).Pasireotide is a somatostatin analog with a stronger affinity for SSTR5 compared to other somatostatin agonists, and is approved for the treatment of Cushing's disease and acromegaly. Buserelin is used for the treatment of esophageal variceal bleeding and AIDS-related diarrhea in patients with liver cirrhosis liver disease. Therefore, regarding the technology of the present invention, exemplary structures of copper-containing trifunctional compounds based on lanreotide derivatives that have an affinity for SSTR2 and can be used for the diagnosis and therapy of the diseases described above are shown below.

[0058] [Chemical formula] (In the formula, "Cu" is 64 Cu +2 or 67 Cu +2 and may be)

[0059] Bombesin is a peptide originally isolated from the skin of the European fire-bellied toad (Bombina bombina). In addition to stimulating gastrin release from G cells, bombesin activates at least three different G protein-coupled receptors: BBR1, BBR2, and BBR3. Such activity includes agonism of such receptors in the brain. Bombesin is also a tumor marker for small cell lung cancer, gastric cancer, gallbladder, pancreatic cancer, and neuroblastoma. Examples of bombesin receptor agonists include, but are not limited to, BBR-1 agonists, BBR-2 agonists, and BBR-3 agonists. Exemplary structures of copper-containing trifunctional compounds that have an affinity for bombesin and can be used for the diagnosis and therapy of the above cancers are shown below.

[0060] [Chemical formula] (In the formula, "Cu" is 64 Cu +2 or 67 Cu +2 and may be)

[0061] Therefore, the tumor targeting domain of any embodiment disclosed herein may include a modified antibody, a modified antibody fragment, a modified binding peptide, a prostate-specific membrane antigen ("PSMA") binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seplase-binding compound, or one or more binding fragments thereof. Examples of tumor targeting domains in any embodiment disclosed herein include belimumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasdotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, and trastuzumab. Buemtansine, siltuximab, semiprimab, nivolumab, pembrolizumab, olaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-Aflivercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, xixtumumab, girentuximab, nimotuzumab, catumakisomab, or etalacizumab are examples of drugs that can be used. The tumor targeting domains of any embodiment disclosed herein include belimumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasdotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, and trastuzumab M. Antigen-binding fragments of tansine, siltuximab, cemiplimab, nivolumab, pembrolizumab, olaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-Afrivercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, xixtumumab, gylenetuximab, nimotuzumab, catumakisomab, or etalacizumab can be listed.

[0062] The blood protein-binding domain (BBD) (e.g., albumin-binding domain; albumin-binding moiety) plays a role in regulating the rate of plasma clearance of a compound in a subject, thereby increasing its circulation time and compartmentalizing the cytotoxic effects of a cytotoxin-containing domain and / or the imaging ability of a contrast-enhancing domain in the plasma space, instead of normal organs and tissues capable of expressing the antigen. Without being constrained by theory, this component of a compound is thought to reversibly interact with serum proteins, e.g., albumin and / or cellular elements. The affinity of this blood protein-binding domain (e.g., albumin-binding domain; albumin-binding moiety) to the plasma or cellular components of blood can be designed to affect the residence time of the compound in the blood pool of the subject. In any embodiment herein, the blood protein-binding domain (e.g., albumin-binding domain; albumin-binding moiety) can be designed to reversibly or irreversibly bind to albumin when present in plasma.

[0063] For example, the blood protein binding domain of any aspect or embodiment of this specification may include short-chain fatty acids, medium-chain fatty acids, long-chain fatty acids, myristic acid, substituted or unsubstituted indole-2-carboxylic acids, substituted or unsubstituted thioamides, substituted or unsubstituted 4-oxo-4-(5,6,7,8-tetrahydronaphthalene-2-yl)butanoic acid, substituted or unsubstituted naphthalene acylsulfonamides, substituted or unsubstituted diphenylcyclohexanol phosphate esters, substituted or unsubstituted 4-iodophenylalkanoic acid, substituted or unsubstituted 3-(4-iodophenyl)propionic acid, substituted or unsubstituted 2-(4-iodophenyl)acetic acid, or substituted or unsubstituted 4-(4-iodophenyl)butanoic acid. In any embodiment of this specification, the blood protein binding domain is

[0064] [ka] (In the formula, Y 1 , Y 2 , Y 3, Y 4 , and Y 5 In each occurrence, independently, is H, halo, or alkyl, and X 2 and X 3 (Each of these is independently O or S, t is independently 0, 1, or 2 in each occurrence, u is independently 0 or 1 in each occurrence, v is independently 0 or 1 in each occurrence, and w is independently 0, 1, 2, 3, or 4 in each occurrence, and u and v cannot be the same value.) This may also be the case. Certain representative examples of moieties that bind to the blood protein albumin, which may be included in any embodiment of this specification, are as follows:

[0065] [ka] Includes one or more of the following.

[0066] In any embodiment of the technology of the present invention, the compound may be any one of the compounds of formulas I to V, or a pharmaceutically acceptable salt and / or solvate thereof. [ka] (In the formula, TTD is a tumor targeting domain of any embodiment disclosed herein. BBD is a blood protein binding domain in any embodiment disclosed herein. Sarc is a sarcofadin-containing domain in any of the embodiments disclosed herein. X 1 In each occurrence, independently, the non-existent O, S, NH, -C(O)-, and -C(O)-NR exist. 1 -, -NR 2 -C(O)-, -C(O)-NR 3 -C1-C 12 Alkylene-,-C1-C 12 Alkylene-C(O)-,-C(O)-NR 4 -C1-C 12Alkylene-C(O)-, -arylene-, -heterocyclene-, -O(CH2CH2O) a -,-CH2CH2-O(CH2CH2O) b -,-CH2CH2-O(CH2CH2O) c -CH2CH2-, -O(CH2CH2O) d -CH2CH2-, -C(O)-O(CH2CH2O) e -, -O(CH2CH2O) f -CH2CH2C(O)-,-C(O)-O(CH2CH2O) g -, -C(O)-O(CH2CH2O) h -CH2CH2-, -C(O)-O(CH2CH2O) i -CH2CH2C(O)-, -CH2CH2-O(CH2CH2O) j -CH2CH2C(O)-, -C(O)-NR 5 -CH2CH2O(CH2CH2O) k -, -C(O)-NR 6 -CH2CH2O(CH2CH2O) l -CH2CH2-, -C(O)-NR 7 -CH2CH2O(CH2CH2O) m -CH2CH2C(O)-, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any combination of two or more thereof, where a, b, c, d, e, f, g, h, i, j, k, l, and m are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 in each occurrence, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In each occurrence, independently, it is H, alkyl, or aryl. L 1 In each occurrence, independently, the non-existent O, S, NH, -C(O)-, and -C(O)-NR exist. 8 -, -NR 9 -C(O)-, -C(O)-NR 10 -C1-C 12Alkylene-,-C1-C 12 Alkylene-C(O)-,-C(O)-NR 11 -C1-C 12 Alkylene-C(O)-, -arylene-, -heterocyclene-, -O(CH2CH2O) a’ -,-CH2CH2-O(CH2CH2O) b’ -,-CH2CH2-O(CH2CH2O) c’ -CH2CH2-, -O(CH2CH2O) d’ -CH2CH2-, -C(O)-O(CH2CH2O) e’ -, -O(CH2CH2O) f’ -CH2CH2C(O)-, -C(O)-O(CH2CH2O) g’ -, -C(O)-O(CH2CH2O) h’ -CH2CH2-, -C(O)-O(CH2CH2O) i’ -CH2CH2C(O)-, -CH2CH2-O(CH2CH2O) j’ -CH2CH2C(O)-, -C(O)-NR 12 -CH2CH2O(CH2CH2O) k’ -, -C(O)-NR 13 -CH2CH2O(CH2CH2O) l’ -CH2CH2-, -C(O)-NR 14 -CH2CH2O(CH2CH2O) m’ -CH2CH2C(O)-, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any combination of two or more thereof, where a', b', c', d', e', f', g', h', i', j', k', l', and m' are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 in each occurrence, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 In each occurrence, independently, it is H, alkyl, or aryl. L 2In each occurrence, independently, the non-existent O, S, NH, -C(O)-, and -C(O)-NR exist. 15 -, -NR 16 -C(O)-, -C(O)-NR 17 -C1-C 12 Alkylene-,-C1-C 12 Alkylene-C(O)-,-C(O)-NR 18 -C1-C 12 Alkylene-C(O)-, -arylene-, -heterocyclene-, -O(CH2CH2O) a’’ -,-CH2CH2-O(CH2CH2O) b’’ -,-CH2CH2-O(CH2CH2O) c’’ -CH2CH2-, -O(CH2CH2O) d’’ -CH2CH2-, -C(O)-O(CH2CH2O) e’’ -, -O(CH2CH2O) f’’ -CH2CH2C(O)-, -C(O)-O(CH2CH2O) g’’ -, -C(O)-O(CH2CH2O) h’’ -CH2CH2-, -C(O)-O(CH2CH2O) i’’ -CH2CH2C(O)-, -CH2CH2-O(CH2CH2O) j’’ -CH2CH2C(O)-, -C(O)-NR 19 -CH2CH2O(CH2CH2O) k’’ -, -C(O)-NR 20 -CH2CH2O(CH2CH2O) l’’ -CH2CH2-, -C(O)-NR 21 -CH2CH2O(CH2CH2O) m’’ -CH2CH2C(O)-, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any combination of two or more thereof, where a'', b'', c'', d'', e'', f'', g'', h'', i'', j'', k'', l'', and m'' are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 in each occurrence, R 15 , R 16 , R 17 , R 18 , R19 , R 20 , and R 21 In each occurrence, independently, it is H, alkyl, or aryl. p is independently 0, 1, 2, 3, 4, or 5 in each occurrence. (q is either 1 or 2 in each occurrence.)

[0067] In any embodiment of the technology of the present invention, the tumor targeting domain is [ka] (In the formula, W 1 , W 2 , W 3 , and W 4 These are -C(O)- and -(CH2) respectively, independently. r -, or -(CH2) s -NH-C(O)-, where r is independently 1 or 2 in each occurrence, and s is independently 1 or 2 in each occurrence, P 1 , P 2 , P 3 , P 4 , P 5 , P 6 , P 7 , P 8 , P 9 , P 10 , P 11 , and P 12 (Each of these is independently H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl, and each of o, o', and o'' is independently 0 or 1.) In any embodiment of this specification, P 1 , P 2 , P 3 , P 4 , P 5 , P 6 , P 7 , P 8 , P 9 , P 10 , P 11 , and P 12 Each of these may independently be H or tert-butyl. In any embodiment of this specification, P1 , P 2 , P 3 , P 4 , P 5 , P 6 , P 7 , P 8 , P 9 , P 10 , P 11 , and P 12 Each of these can be H independently.

[0068] The sarcofadin-containing domain of the compound of the present invention is 64 Cu +2 or 67 Cu +2 It is a domain capable of chelating. In any embodiment disclosed herein, the sarcofazine-containing domain is

[0069] [ka] (In the formula, R 22 is H, alkyl, aryl, or NR 23 R 24 And R 23 and R 24 Each of these is independently H, alkyl, aryl, alkanoyl, or aryloyl, and L 3 -C(O)-, -C1-C does not exist. 12 Alkylene-,-C1-C 12 Alkylene-C(O)-,-NR 25 C(O)-C1-C 12 Alkylene-C(O)-,-C1-C 12 Alkilen-NR 25 C(O)-C1-C 12 Alkylene-C(O)-, -Arirene-, -C1-C 12 Alkylene-C(O)NR 25 -CH2-phenylene-CH2-,-C1-C 12 Alkylene-C(O)NR 25 -CH2-phenylene-C(O)-, -C1-C 12 Alkilen-NR 25 C(O)-C1-C12 Alkylene-C(O)-C(O)NR 25 -CH2-phenylene-CH2-, or -C1-C 12 Alkilen-NR 25 C(O)-C1-C 12 Alkylene-C(O)-C(O)NR 25 -CH2-phenylene-C(O)- and R 25 (Each instance is independently H, alkyl, or aryl.) This may also be the case. In any embodiment of this specification, R 22 is also H, methyl, or NH2. In any embodiment of this specification, the sarcofadin-containing domain of the compound is 64 Cu +2 or 67 Cu +2 It can be chelated.

[0070] The present invention also provides compositions and pharmaceuticals comprising any one embodiment of the compound of the present invention and a pharmaceutically acceptable carrier or one or more excipients or fillers (collectively referred to as the “pharmaceutically acceptable carrier” unless otherwise specified). The compositions can be used in the methods and treatments described herein. The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and an effective amount of any one compound of any embodiment of the compound of the present invention for imaging and / or treating a condition, wherein the condition may include one or more of non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumor, pituitary tumor, vasoactive enteropeptide-secreting tumor, glioma, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer. For example, such conditions may include mammalian tissues that overexpress PSMA, such as cancers expressing PSMA (including cancerous tissue, cancer-associated neovascular structures, or combinations thereof), Crohn's disease, or IBD.

[0071] In further relevant embodiments, imaging methods are provided, comprising the steps of administering (e.g., administering an effective amount) one compound from any of the compound embodiments and embodiments of the Art of the Invention, or administering a pharmaceutical composition comprising an effective amount of one compound from any of the compound embodiments and embodiments of the Art of the Invention, to a subject, and after administration, detecting positron emission, detecting gamma rays from positron emission and annihilation (e.g., by positron emission tomography), and / or detecting Cherenkov rays from positron emission (e.g., Cherenkov emission imaging). In any embodiment of the imaging method, the subject may be suspected of having one or more of the following conditions: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumor, pituitary tumor, vasoactive enteropeptide-secreting tumor, glioma, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, metastatic cancer, mammalian tissue overexpressing PSMA, e.g., cancer expressing PSMA (including cancerous tissue, cancer-associated neovascular structures, or combinations thereof), Crohn's disease, or IBD. The detection step may occur, for example, during surgical removal of mammalian tissue overexpressing PSMA. The detection step may include performing the detection step using a handheld device. For example, Cherenkov emission images can be obtained by detecting Cherenkov light using an ultra-sensitive optical camera, such as an electron-multiplier charge-coupled device (EMCCD) camera.

[0072] In any of the embodiments described above, the effective amount can be determined in relation to the subject. "Effective amount" means the amount of compound or composition required to produce the desired effect. One non-limiting example of an effective amount is, but is not limited to, an amount or dose that results in an acceptable level of toxicity and bioavailability for therapeutic (pharmaceutical) use, including the treatment of one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (e.g., castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancers. Another example of an effective dose is an amount or dose capable of reducing symptoms associated with one or more of the following cancers: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (e.g., castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancers, for example, an amount or dose capable of reducing proliferation and / or metastasis. The effective amount of the compounds of the present invention may include, but is not limited to, an amount sufficient to enable detection of binding of the compounds to important targets including one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (e.g., castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancers.Another example of an effective dose includes amounts or doses capable of providing detectable gamma-ray emissions from positron emission and annihilation (higher than background) in subjects having tissues containing overexpressed PSMA, such as one or more of the statistically significant emissions above the background, including non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (e.g., castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, metastatic cancer, and overexpressed PSMA, such as one or more of the statistically significant emissions above the background. Another example of an effective amount includes an amount or dose capable of providing Cherenkov emission detectable by positron emission (higher than background) in subjects having tissues containing overexpressing PSMA, such as non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (e.g., castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, metastatic cancer, and overexpressing PSMA, for example, one or more statistically significant emissions above the background. An effective amount is about 0.01 μg to about 1 mg of the compound per gram of composition, preferably about 0.1 μg to about 500 μg of the compound per gram of composition.

[0073] As used herein, “subject” or “patient” refers to a mammal, such as a cat, dog, rodent, or primate. Typically, the subject is a human, preferably a human who has or is suspected of having one or more of the following cancers: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (e.g., castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer. The terms “subject” and “patient” may be used interchangeably.

[0074] In particular, the effective amount of the compound of any embodiment of this specification for treating one or more of the following cancers (e.g., non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (e.g., castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancers) and / or mammalian tissues overexpressing PSMA may be about 0.1 μg to about 50 μg per kilogram of mass of the subject. Therefore, cancer (for example, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (for example, castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and The effective amount of the compound of any embodiment described herein for treating one or more of the following (and metastatic cancers) and / or mammalian tissues overexpressing PSMA is about 0.1 μg / kg, about 0.2 μg / kg, about 0.3 μg / kg, about 0.4 μg / kg, about 0.5 μg / kg, about 0.6 μg / kg, about 0.7 μg / kg, about 0.8 μg / kg, about 0.9 μg / kg, about 1 μg / kg, about 2μg / kg, about 3μg / kg, about 4μg / kg, about 5μg / kg, about 6μg / kg, about 7μg / kg, about 8μg / kg, about 9μg / kg, about 10μg / kg, about 11μg / kg, about 12μg / kg , about 13μg / kg, about 14μg / kg, about 15μg / kg, about 16μg / kg, about 17μg / kg, about 18μg / kg, about 19μg / kg, about 20μg / kg, about 22μg / kg, about 24μg / kg It may be approximately 26 μg / kg, approximately 28 μg / kg, approximately 30 μg / kg, approximately 32 μg / kg, approximately 34 μg / kg, approximately 36 μg / kg, approximately 38 μg / kg, approximately 40 μg / kg, approximately 42 μg / kg, approximately 44 μg / kg, approximately 46 μg / kg, approximately 48 μg / kg, approximately 50 μg / kg, or it may include any two of these values ​​and / or be in any range between any two of these values.

[0075] In particular, the effective amount of the compound of any embodiment of this specification for imaging mammalian tissue overexpressing PSMA (e.g., cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (e.g., castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer) and / or PSMA may be about 0.1 μg to about 50 μg per kilogram of mass of the subject. Therefore, cancer (for example, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (for example, castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, The effective amounts of the compounds of any embodiment described herein for treating one or more of the following: and metastatic cancers and / or mammalian tissues overexpressing PSMA are approximately 0.1 μg / kg, approximately 0.2 μg / kg, approximately 0.3 μg / kg, approximately 0.4 μg / kg, approximately 0.5 μg / kg, approximately 0.6 μg / kg, approximately 0.7 μg / kg, approximately 0.8 μg / kg, approximately 0.9 μg / kg, approximately 1 μg / kg, and approximately 2 μg / kg. μg / kg, approximately 3 μg / kg, approximately 4 μg / kg, approximately 5 μg / kg, approximately 6 μg / kg, approximately 7 μg / kg, approximately 8 μg / kg, approximately 9 μg / kg, approximately 10 μg / kg, approximately 11 μg / kg, approximately 12 μg / kg, Approximately 13μg / kg, approximately 14μg / kg, approximately 15μg / kg, approximately 16μg / kg, approximately 17μg / kg, approximately 18μg / kg, approximately 19μg / kg, approximately 20μg / kg, approximately 22μg / kg, approximately 24μg / kg, It may be approximately 26 μg / kg, approximately 28 μg / kg, approximately 30 μg / kg, approximately 32 μg / kg, approximately 34 μg / kg, approximately 36 μg / kg, approximately 38 μg / kg, approximately 40 μg / kg, approximately 42 μg / kg, approximately 44 μg / kg, approximately 46 μg / kg, approximately 48 μg / kg, approximately 50 μg / kg, or it may include any two of these values ​​and / or be in any range between any two of these values.

[0076] The compounds of the present invention may also be administered to a patient together with other conventional contrast agents that may be useful in imaging and / or treating one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (e.g., castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, metastatic cancer, or mammalian tissues that overexpress PSMA. Such mammalian tissues include, but are not limited to, cancers expressing PSMA (including cancer tissue, cancer-associated neovascular structures, or combinations thereof), Crohn's disease, or IBD. Therefore, the pharmaceutical compositions and / or methods of the present invention may further include contrast agents different from the compounds of the present invention. The pharmaceutical compositions and / or methods of the present invention may include therapeutic agents different from the compounds of the present invention. The pharmaceutical compositions and / or methods of the present invention may further include a contrast agent according to any embodiment of the compounds of the present invention, and similarly a therapeutic agent according to any embodiment of the compounds of the present invention. The compounds according to the present invention may be both therapeutic agents and contrast agents. Administration may include oral administration, parenteral administration, or nasal administration. In any of these embodiments, administration may include subcutaneous injection, intravenous injection, intraperitoneal injection, or intramuscular injection. In any of these embodiments, administration may include oral administration. The methods of the present invention may also include administering, sequentially or in combination with one or more of the compounds of the present invention, a conventional contrast agent in an amount that may be potentially or synergistically effective against imaging one or more of the following mammalian tissues: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (e.g., castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, metastatic cancer, and mammalian tissues overexpressing PSMA.

[0077] In any embodiment of the technology of the present invention described herein, the pharmaceutical composition may be packaged in unit dosage forms. These unit dosage forms are effective in treating one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (e.g., castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancers. Generally, the unit dose containing the compounds of the technology of the present invention will vary depending on the patient's considerations. Such considerations include, for example, age, protocol, condition, sex, disease severity, contraindications, and concurrent treatments. Exemplary unit doses based on these considerations may also be adjusted or modified by physicians in the art. For example, a unit dose to a patient containing the compounds of the technology of the present invention may be 1 × 10⁻⁶ -4 g / kg to 1g / kg, preferably 1 × 10 -3 The dosage can vary from g / kg to 1.0 g / kg. The dosage of the compound in the present invention can also vary from 0.01 mg / kg to 100 mg / kg, or preferably from 0.1 mg / kg to 10 mg / kg. Suitable unit dosage forms, but not limited to these, include powders, tablets, pills, capsules, lozenges, suppositories, patches, nasal sprays, injections, implantable sustained-release formulations, mucosal films, topical varnishes, and lipid complexes.

[0078] Pharmaceutical compositions can be prepared by mixing one or more compounds of the technology of the present invention with pharmaceutically acceptable carriers, excipients, binders, diluents, etc., for the purpose of preventing and treating disorders associated with cancer (e.g., one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (e.g., castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancers). The compounds and compositions described herein can be used to prepare formulations and agents for the treatment of one or more of the following cancers: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer (e.g., castration-resistant prostate cancer), neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancers. Such compositions may be in the form of granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions, or liquids. The compositions of the present invention can be formulated for various routes of administration, such as oral, parenteral, topical, rectal, nasal, vaginal, or via implanted reservoir. Parenteral or systemic administration may include, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular injection. The following dosage forms are provided as examples and should not be construed as limiting the technology of the present invention.

[0079] For oral, intraoral buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gel caps, and caplets are acceptable solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the technology of the present invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive, such as starch or other additives. Suitable additives include sucrose, lactose, cellulose sugars, mannitol, maltitol, dextran, starch, agar, alginates, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers, or glycerides. Optionally, the oral dosage form may contain other components that aid in administration, such as inert diluents or lubricants, such as magnesium stearate, or preservatives, such as parabens or sorbic acid, or antioxidants, such as ascorbic acid, tocopherol or cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavorings or fragrances. Tablets and pills may be further treated with suitable coating materials known in the art.

[0080] Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and liquids, which may contain an inert diluent, such as water. Pharmaceutical preparations and drugs may also be prepared as liquid suspensions or solutions using sterile liquids, for example, oils, water, alcohols, and combinations thereof, but not limited to these. Pharmaceutically appropriate surfactants, suspending agents, and emulsifiers may also be added for oral or parenteral administration. As described above, the suspension may contain oil. Examples of such oils, but not limited to, include peanut oil, sesame oil, cottonseed oil, corn oil, and olive oil. The suspension preparation may also contain fatty acid esters, such as ethyl oleate, isopropyl myristate, fatty acid glycerides, and acetylated fatty acid glycerides. The suspension formulation may also contain alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol, and propylene glycol. Ethers, such as, but not limited to, poly(ethylene glycol), petroleum hydrocarbons, such as mineral oil and petrolatum; and water may also be used in the suspension formulation.

[0081] Injectable dosage forms generally include aqueous or oily suspensions, which can be prepared using appropriate dispersants or wetting agents and suspending agents. Injectable forms may also be in the form of a solution phase or suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterile water, Ringer's solution, or isotonic aqueous saline. Alternatively, sterile oils can be used as solvents or suspending agents. Typically, oils or fatty acids are non-volatile and include natural or synthetic oils, fatty acids, monoglycerides, diglycerides, or triglycerides. For injection, the pharmaceutical formulation and / or drug may be a powder suitable for reconstitution with appropriate solutions as described above. Examples of these include, but are not limited to, lyophilized, tumble-dried, or spray-dried powders, amorphous powders, granules, precipitates, or particles. For injection, the formulation may optionally contain stabilizers, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof.

[0082] The compounds of the present invention may be administered to the lungs by inhalation via the nose or mouth. Suitable pharmaceutical formulations for inhalation include any solvent and optionally other compounds, such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof, in the form of liquids, sprays, dry powders, or aerosols. Carriers and stabilizers vary depending on the requirements of the specific compound but typically include nonionic surfactants (Tweens, Pluronic, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars, or sugar alcohols. Aqueous and non-aqueous (e.g., fluorocarbon sprays) aerosols are commonly used for inhalation delivery of the compounds of the present invention.

[0083] In addition to the representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the art of the present invention. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference. The compositions of the present invention may also include, for example, micelles or liposomes, or some other encapsulation forms.

[0084] Specific doses can be adjusted according to the disease state, the subject's age, weight, overall health, sex, and diet, dose interval, route of administration, elimination rate, and drug combination. Any of the above dosage forms containing an effective amount are well within the scope of routine experimentation and therefore well within the scope of the present invention. The therapeutic effectiveness of treatment using the technology of the present invention can be easily determined by utilizing various assays and model systems. For the indicated condition, the test subject will show a 10%, 20%, 30%, 50%, or more substantial reduction, up to 75-90%, or 95% or greater reduction in one or more symptoms caused by or associated with the disorder in the subject, compared to a placebo-treated or other appropriate control subject.

[0085] The examples herein illustrate the advantages of the technology of the present invention and are provided to further assist those skilled in the art in preparing or using compounds or salts thereof, pharmaceutical compositions, derivatives, prodrugs, or tautomers of the technology of the present invention. The examples herein are also presented to more fully illustrate preferred embodiments of the technology of the present invention. The examples shall not be construed as limiting the scope of the technology of the present invention as defined by the appended claims. The examples may include or incorporate any variation, aspect, or embodiment of the technology of the present invention described above. The variations, aspects, or embodiments described above may also each further include or incorporate variations of any or all other variations, aspects, or embodiments of the technology of the present invention. [Examples]

[0086] Materials and equipment. All solvents and reagents, unless otherwise specified, were purchased from commercial sources and used untreated and without further purification. Solvents marked "dried" were obtained after storage on 3 Å molecular sieves. The reactions were monitored by thin-layer chromatography (TLC, Whatman UV254 aluminum-supported silica gel).

[0087] RPS-085, [ 64 Cu]Cu-RPS-085 and [ 67 Synthesis of Cu]Cu-RPS-085 The trifunctional scaffold (((S)-5-(3-(3-(1-((14S,17S)-14-(4-aminobutyl)-17-carboxy-24-(4-iodophenyl)-12,15,23-trioxo-3,6,9-trioxa-13,16,22-triazatetracosyl)-1H-1,2,3-triazole-4-yl)phenyl)ureido)-1-carboxypentyl)carbamoyl)-L-glutamic acid was synthesized as described in Kelly et al., (Eur J Nucl Med Mol Imaging. 2018;45:1841-51). This amine (13 mg, 10 μmol, 1 equivalent) was dissolved in anhydrous DMF (1 mL; SIGMA Aldrich, USA) and stirred with N,N-diisopropylethylamine (18 μL, 100 μmol, 10 equivalents) at room temperature (rt) for 5 minutes. The binding of the sarcofadin chelating agent to the scaffold is controlled by the NHS ester derivative of MeCOSar and Lys. ε This was achieved through a reaction between [components]. An overview of this synthesis is provided below:

[0088] [ka] A solution of MeCOSar N-succinimidyl ester (6.2 mg, 12 μmol, 1.2 equivalents) in DMF (0.5 mL) was added dropwise to the reactants, and the resulting mixture was stirred at rt for 5 hours. The crude mixture was purified by HPLC using a dual-pump Agilent 1200 Series HPLC with a Phenomenex Luna® C18(2) 100 Å, 250 cm × 21.2 mm I.D., 10 μm reversed-phase column. The mobile phase was a gradient from 10% acetonitrile (MeCN) / water (H2O) + 0.05% trifluoroacetic acid (TFA) to 90% MeCN / H2O + 0.05% TFA over 40 minutes at a flow rate of 12 mL / min. The peak corresponding to RPS-085 was collected and lyophilized. RPS-085 was isolated as a white powder (8.6 mg, 53%).

[0089] The purity of the product was confirmed by analytical HPLC using a dual-pump Agilent ProStar HPLC equipped with an Agilent ProStar 325 dual-wavelength UV-Vis detector (Agilent Technologies, USA). UV absorption was monitored at 220 nm and 280 nm. Analysis was performed using a gradient method at a flow rate of 2 mL / min on an XSelect® CSH® C18 5 μm 4.6 × 50 mm column (Waters, USA). The gradients were: 0–1 min: 0%B; 1–8 min: 0–100%B; 8–9 min: 100%B; 9–10 min: 100–0%B. Mobile phase A consisted of H2O + 0.01% v / v TFA (Sigma Aldrich, USA), and mobile phase B consisted of 90% v / v MeCN / H2O + 0.01% TFA. Product identification information was confirmed by mass spectrometry. The mass was determined using a Waters ACQUITY UPLC® coupled to a Waters SQ Detector 2 (Waters, USA). MS(ESI+): 1620.14. Calculated mass: 1618.74.

[0090] Compared to the parent compound RPS-063, the affinity of the generated RPS-085 compound for PSMA decreased by approximately an order of magnitude. RPS-085, which does not contain metal, is used in IC55. 50 It inhibited PSMA at =29.1±2.4 nM. Its affinity for human serum albumin (HSA) was also K d The reduction was 9.9 ± 1.7 μM.

[0091] [ 64 Cu]Cu-RPS-085 was quantitatively radiolabeled in both 10X PBS (pH 7.4) and 0.5M NH4OAc (pH 5.5) at 25°C for 20 minutes (n=6). Labeling with 3N NaOAc (pH 4.5) was achieved at the same temperature with a yield of 35±2% (n=2). 64 Cu]CuCl2 was purchased from the University of Wisconsin as a diluted solution in HCl. 64A Cu]CuCl2 solution (50–100 μL, containing 350–800 MBq) was transferred to an Eppendorf tube and diluted with 300 μL of 0.5 M NH4OAc. To this solution, 5 μL of 1 mg / mL RPS-085 in DMSO was added. The reaction mixture was incubated at 25°C for 20 minutes in an Eppendorf ThermoMixer® C (VWR, USA). The sample was then diluted to 10 mL with H2O and passed through a pre-prepared Sep-Pak C18 Plus Light cartridge (Waters, USA). The reaction vessel and cartridge were washed with 5 mL of H2O. The radioactivity retained on the cartridge was eluted with 100 μL of EtOH (300 proof; VWR, USA), followed by elution with 900 μL of physiological saline (0.9% NaCl solution; VWR, USA). Radiochemical purity was determined by analytical reversed-phase (radioactive) HPLC using a dual-pump Varian Dynamax HPLC system (Agilent Technologies, USA) equipped with dual UV-Vis detectors, and by a NaI(Tl) flow count detector (Bioscan, USA). UV absorption was monitored at 220 nm and 280 nm. Analysis was performed using a gradient method at a flow rate of 2 mL / min on a Symmetry C18 column (5 μm, 4.6 × 50 mm, 100 Å; Waters, USA). The gradient and mobile phase compositions were the same as those described above. Molar radioactivity was [ 64 Cu]Cu 2+ It was altered by the radioactivity. If the initial radioactivity was 800 MBq, [ 64 Cu]Cu-RPS-085 was isolated with a molar radioactivity of 117 GBq / μmol and radiochemical purity >99% (Figures 1A-1B).

[0092] [ 67Cu]Cu-RPS-085 was quantitatively radiolabeled at a concentration of 6.2 μM in 0.1 M NH4OAc at 25°C for 20 minutes. The pH of the reaction mixture was approximately 6. Cu-67 was supplied by the Isotope Program of the Office of Nuclear Physics, Department of Energy's Office of Science. The radioactivity was diluted in 100 μL of 0.1 M NH4OAc to achieve a radioactivity concentration of approximately 4 GBq / mL. A 60 μL aliquot of the solution (containing 245 MBq) was added to a 1 mg / mL solution of RPS-085 in DMSO, which was diluted in 930 μL of 0.1 M NH4OAc. The reaction mixture was incubated in an Eppendorf ThermoMixer® C (VWR, USA) at 25°C for 20 minutes. Next, the sample was diluted to 10 mL with H2O and passed through a pre-prepared Sep-Pak C18 Plus Light cartridge (Waters, USA). The reaction vessel and cartridge were washed with 5 mL of H2O. The radioactivity retained on the cartridge was eluted with 200 μL of EtOH (300 proof; VWR, USA), followed by elution with 1.8 mL of physiological saline (0.9% NaCl solution; VWR, USA). The radiochemical purity was determined by analytical reversed-phase (radioactive) HPLC as described above. At an initial radioactivity of 245 MBq, [ 67 Cu]Cu-RPS-085 was isolated with a molar radioactivity of 41 GBq / μmol and radiochemical purity >99% (Figures 2A-2B). For comparison, under the same labeling conditions, [ 67 Cu]Cu-RPS-063 was isolated with a radiochemical yield of 43% and a radiochemical purity of >99%.

[0093] Stability testing of compounds Reformed [ 64The stability of the Cu]Cu-RPS-085 solution was determined by triple replication at 25°C. Three 1 mL samples were transferred to Eppendorf tubes (VWR, USA) at a radioactivity concentration of approximately 10 MBq / mL and radiochemical purity >99%. The samples were incubated at 25°C for 24 hours in an Eppendorf ThermoMixer® C (VWR, USA). Radiochemical purity was determined by analytical reverse-phase (radioactive) HPLC and expressed as a fraction of the purity of the sample before incubation. After reformation, [ 64 Cu]Cu-RPS-085 remained stable at room temperature for longer than 24 hours.

[0094] [ 67 The plasma stability of Cu]Cu-RPS-085 was determined by a previously described method (Alt, et al., Mol Pharmaceutics. 2014; 11: 2855-63). Briefly, frozen human plasma was purchased from Sigma Aldrich (USA), thawed at 37°C, and 200 μL aliquots were transferred to Eppendorf tubes. 100 μL aliquots were then mixed in 10% EtOH / saline. 67 Cu]Cu-RPS-085 was added to each tube, and the mixture was shaken at 300 rpm at 37°C for 24 hours using an Eppendorf ThermoMixer® C (VWR, USA). The experiment was performed in triple replicates. Protein precipitation was achieved by adding 600 μL of acetonitrile. The sample was centrifuged at 13500 rpm for 3 minutes in an Eppendorf 5424-R Centrifuge. The supernatant was analyzed by analytical reverse-phase (radioactive) HPLC as described above. After 24 hours of incubation in human plasma, [ 67 Cu]Cu-RPS-085 was 97.4±0.4% intact. The only radiochemical impurity was an unidentified fragment of the parent compound. It did not form a complex. 67 Cu]Cu 2+ It was not observed.

[0095] cell culture, IC 50 In vitro determination and affinity for human serum albumin The PSMA-expressing human prostate cancer cell line, LNCaP, was obtained from the American Type Culture Collection. Cell culture supplies were obtained from Invitrogen (USA) unless otherwise specified. LNCaP cells were maintained at 37°C / 5% CO2 in a humidified incubator in RPMI-1640 medium supplemented with 10% fetal bovine serum (Hyclone), 4 mM L-glutamine, 1 mM sodium pyruvate, 10 mM N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES), 2.5 mg / mL D-glucose, and 50 μg / mL gentamicin. Cells were removed from flasks for passage or transfer to 12-well assay plates and incubated with 0.25% trypsin / ethylenediaminetetraacetic acid (EDTA).

[0096] RPS-085 IC that does not contain metal 50 teeth, 99m In a multi-concentration competitive binding assay for Tc-MIP-1427 (Hillier et al., J Nucl Med. 2013; 54: 1369-76), binding to PSMA on LNCaP cells was determined according to a previously described method (Kelly et al., Eur J Nucl Med Mol Imaging. 2018; 45: 1841-51). RPS-085 was added to the wells at final concentrations ranging from 1 pM to 10 μM. The assay was performed in triple replicates, and IC was determined. 50 This was expressed as the mean ± standard deviation.

[0097] The affinity for human serum albumin was determined by high-performance affinity chromatography, as previously described (Kelly et al., J Nucl Med. 2019; 60: 656-63). Briefly, with a maximum injection mass of 80 ng and a maximum injection volume of 20 μL, [ 67Cu]Cu-RPS-085 was packed into a Chiralpak HSA analytical high-performance liquid chromatography column, 100 × 2 mm, 5 mm (Daicel Corp.) as a solution in 10% v / vEtOH / physiological saline. A homogeneous mobile phase of 5% v / v isopropanol / 0.067 M phosphate buffer was used at pH 7.4 at a constant flow rate of 0.3 mL / min, and the analysis was performed in quadruple replicates. 67 The retention time for Cu]Cu-RPS-085 was 4.64 ± 0.52 minutes. The equation previously derived for the analytical conditions is:

[0098]

number

[0099] LNCaP xenograft mouse model and micro-PET / CT imaging All animal experiments were approved by the Institutional Animal Care and Use Committee of Weill Cornell Medicine and conducted in accordance with the guidelines outlined in the USPHS Policy on Humane Care and Use of Laboratory Animals. Mice were housed in an approved facility under standard conditions with a 12-hour light / dark cycle. Food and water were freely provided throughout the experimental process. Male BALB / c athymia nu / nu mice were purchased from Jackson Laboratory (USA). Before inoculation, 4 × 10⁶ LNCaP cells were administered. 7Cells were suspended at a density of cells / mL in a 1:1 mixture of PBS (VWR, USA) and Matrigel (BDBiosciences, USA). Each mouse received 0.25 mL of the cell suspension subcutaneously into the left flank. Animals were monitored twice a week until a palpable tumor appeared. LNCaP xenograft tumors are [ 64 This was clearly visualized with Cu]Cu-RPS-085 (Figure 3). Renal clearance was the primary pathway for elimination, resulting in initial uptake of the compound in the kidneys and bladder. Background tissue radioactivity was low. Uptake in tumors and kidneys was predicted by drawing ROIs around each tissue. According to this semi-quantitative method, radioactivity within the tumor was highest at 3-hour pi but remained substantially stable over the 48-hour imaging window. By 6-hour pi, uptake in the tumor had surpassed that of the kidneys, and by 24 hours, only the tumor could be visualized by micro-PET / CT.

[0100] Tumor size is 200-500 mm 3 When the range was reached, the mice (n=4) had 21.2±0.5MBq[ 64 Cu]Cu-RPS-085 was administered intravenously. The total mass of the dose received by each animal was approximately 300 ng (185 pmol). Mice were anesthetized with isoflurane and imaged with micro-PET / CT (Inveon®; Siemens Medical Solutions, USA) at 1, 3, 6, 24, and 48 hours after injection (pi). The total acquisition time was 30 minutes. A CT scan was obtained immediately before the PET acquisition for both anatomical co-registration and attenuation correction. Images were reconstructed using Inveon® software provided by the vendor.

[0101] Biomedical distribution and dose measurement The tumor size is approximately 200 mm. 3 Once it reaches this point, the mouse (n=4 / time point) receives 3.8±0.1MBq[ 64 Cu]Cu-RPS-085 or 0.8±0.005MBq[67 Cu]Cu-RPS-085 was administered by intravenous injection. The total mass of the dose received by each animal was [ 64 Cu]Cu-RPS-085 and [ 67 For the experiment with Cu]Cu-RPS-085, the amounts were approximately 50 ng (31 pmol) and approximately 28 ng (17 pmol), respectively. The mice were ([ 64 Cu]Cu-RPS-085) for 4 hours, 24 hours, or 48 hours pi or ([ 67 The animals were euthanized at 4, 24, and 96 hours pi of Cu]Cu-RPS-085. Blood samples were collected, and the following tissues were collected and weighed by wet mass using a digital balance: heart, lungs, liver, stomach, small intestine, large intestine, spleen, pancreas, kidneys, muscle, bone, and tumor. Tissue was counted against a 1% injection volume of the standard using a Wizard2 Automatic Gamma Counter (Perkin Elmer, USA). The counts were corrected for decay and injected radioactivity, and tissue uptake was expressed as a percentage per gram of injected dose (%ID / g). The mean standard error (SEM) was calculated for each data point. Statistical analysis was performed using an unpaired t-test with GraphPadPrism software. P values ​​of 0.05 or less were considered significant. Table 1 below shows the concentrations of [67Cu]Cu-RPS-085 found in the blood, heart, lungs, liver, small intestine, large intestine, stomach, spleen, pancreas, kidneys, muscles, and bones at 4, 24, and 96 hours after injection (n=4 per time point). Published values ​​for [177Lu]Lu-RPS-063 are shown for comparison; all concentrations are expressed as a percentage of the amount injected per organ.

[0102] [Table 1]

[0103] Data for dose measurement calculations were based on the average of 4-5 animals at 4, 24, and 96 hours after each injection. Percentages of injected dose per organ were first obtained in the blood, heart, lungs, liver, small intestine, large intestine, stomach, spleen, pancreas, kidneys, muscle, bone, tumor, and tail. Biodistribution data were fitted using a power function over the first 96 hours. Concentrations were interpolated at 2-hour intervals using the power function for each organ to obtain better predictions of the rate. The integration time was further extended by 96 hours, assuming that the percentage of injected dose per organ remained constant after the first 96 hours, and that the only change in concentration between 96 and 192 hours was due to radioactive decay. The integral was then obtained at 2-hour intervals using a trapezoidal approximation. The interval integral was scaled to a complete integral to obtain better predictions. These residence times were used to predict absorbed doses to human subjects using an adult human male model with the OLINDA program without bladder clearance. The doses to the remaining body parts were not used in this calculation.

[0104] In tumors and tumor-to-background ratios, [ 64 The uptake of Cu]Cu-RPS-085 was quantified after biological distribution experiments. Figure 4 shows the uptake of [Cu]Cu-RPS-085 in male Balb / Cnu / nu mice carrying LNCaP xenotransplantation. 64 This shows the biological distribution of Cu]Cu-RPS-085. In mice (n=4 / time point), 3.8±0.1 MBq[ 64Cu]Cu-RPS-085 was administered intravenously, and the subjects were sacrificed at 4, 24, or 48 hours prior to administration. The radioactivity of each tissue was determined by comparison with a 1% ID radioactivity standard and expressed as %ID / g ± SEM. Statistical significance is indicated by * (P < 0.05) and ** (P < 0.01). Peak tumor uptake was observed at 4 hours prior to administration (12.9 ± 1.4% ID / g), but clearance at 24 hours prior to administration (8.3 ± 0.8% ID / g) and 48 hours prior to administration (9.8 ± 1.3% ID / g) was not statistically significant (P > 0.15). In comparison, radioactivity in the kidney was eliminated from 13.7 ± 2.3% ID / g at 4 hours prior to administration to 2.4 ± 0.4% ID / g at 24 hours prior to administration, and further clearance to 1.6 ± 0.1% ID / g at 48 hours prior to administration. Radioactivity in all other tissues, including the liver, was less than 0.5% ID / g at all time points. 64 The distribution of Cu]Cu-RPS-085 resulted in a tumor-to-kidney ratio of 0.9±0.2 at 4-hour pi, which significantly increased to 3.4±0.7 at 24-hour pi and 6.1±0.8 at 48-hour pi (P<0.02). The tumor-to-blood ratio was 230±33 at 4-hour pi and exceeded 400. The tumor-to-muscle ratio exceeded 500 at all observed time points.

[0105] Figure 5 shows the [ 67 This shows the biological distribution of Cu]Cu-RPS-085. In mice (n=4 / time point), 0.8±0.005 MBq[ 67 Cu]Cu-RPS-085 was administered intravenously, and the animals were sacrificed at 4-hour, 24-hour, or 96-hour pi. Radioactivity in each tissue was determined by comparison with a 1% ID radioactivity standard and expressed as %ID / g ± SEM. Statistical significance is indicated by * (P<0.05) and ** (P<0.01). 67 The biological distribution of Cu]Cu-RPS-085 was observed at 4-hour and 24-hour time intervals. 64The biodistribution of Cu]Cu-RPS-085 closely mimics that of tumors. The primary tissues where the radioactive ligand accumulated were tumors and kidneys (Figure 5). At these time points, tumor uptake was 12.5±2.7%ID / g and 7.9±0.9%ID / g, respectively. Radioactivity in the kidney was 19.7±5.0%ID / g and 4.5±0.8%ID / g, respectively. These values ​​are [ 64 The values ​​obtained were not significantly higher than those obtained in the Cu]Cu-RPS-085 experiment (P>0.06). By 96 hours pi, the radioactivity in the tumor had decreased to 5.1±3.3%ID / g, and the radioactivity in the kidney was 1.7±0.3%ID / g. At this point, the tumor-to-kidney ratio was 3.0±0.5. The predicted absorbed dose to the tumor over 192 hours was 14319 mSv / MBq. In comparison, the dose absorbed by the kidney was 884 mSv / MBq, representing a reduction of at least 1 / 16. The total absorbed dose was 14.5 mSv / MBq, and no other tissue exceeded 65 mSv / MBq (Table 2).

[0106] [Table 2]

[0107] PSMA-targeted imaging and staging for primary prostate cancer and recurrent disease 68 The values ​​for Ga-labeled small molecules are becoming well established. Nevertheless, the short half-life (t) of this radioactive isotope remains a concern. 1 / 2 (=68 minutes) prevents the quantification of radioactive ligand distribution beyond several hours post-injection. Consequently, gallium-68 is an incomplete fit for predicting pre-therapy dose measurements prior to targeted radioactive ligand therapy using lutetium-177 (t 1 / 2 =6.65 days). Therefore, to quantify the radioactive ligand distribution and predict the absorbed dose, In-111(t) is used as a substitute for Lu-177. 1 / 2Dosimetry experiments can also be conducted using (=2.81 days) or using low-dose Lu-177 itself. These experiments increase the number of times radioactive material is administered to the patient and may suffer from lower imaging accuracy compared to PET imaging using Ga-68. In addition, even if the delivery vector is the same 、68 Ga-, 111 In-, and 177 The distribution of Lu-labeled radioligands can vary. From this perspective, it is preferable to use "sister" radioisotopes, such as Y-86 / Y-90, Sc-44 / Sc-47, and Cu-64 / Cu-67, for quantitative imaging and therapy. The physical properties of copper-64 and copper-67, including well-matched half-lives, emission of short-range particles with ideal energy for PET imaging and therapy, and the absence of simultaneous photon emission (Table 3), are ideal for theranostic use. Furthermore, the high radioactivity of these two radionuclides can be obtained with high radionuclide purity. This allows for the use of: 64 / 67 This facilitates the supply of Cu-labeled radioactive ligands to centers located far from production sites.

[0108] [Table 3]

[0109] To fully utilize the potential of Cu-64 / Cu-67 theranostics, efficient and stable chelation of radioactive metals is necessary. In contrast, 64 The Cu(II)-DOTA complex is probably 64 Cu(II) 64 Although it is unstable in vivo as a result of reduction to Cu(I), the cross-linked macrocyclic chelating agent exhibits greater complex stability. The bifunctionalized 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane is known as a chelating agent and sarcofadin, and when conjugated to a peptide or peptide dimer, 64 Cu 2+It has been shown to form an extremely stable complex. The applicants have confirmed that the MeCOSar chelating agent enables the rapid and efficient labeling of small molecules RPS-085 at low concentrations (<10 μM) with either copper 64 or copper 67 under mild conditions. Ligand concentration 10 -7 M or Cu 2+ MeCOSar's ability to quantitatively complexize compounds is a major advantage of MeCOSar over other commercially available chelating agents, as it can be translated into a substantial increase in the molar radioactivity of radiolabeled compounds. 64 / 67 Cu]Cu-RPS-085 is stable in solution for longer than 24 hours at room temperature. This is because it is stable in the field. 68 Ge / 68 It supports centralized production and distribution to centers that do not have a Ga generator. The radioactive ligand is stable in human plasma for longer than 24 hours at 37°C, [ 64 / 67 Cu]Cu 2+ The absence of radioactivity in the mouse liver, a major organ where radioactivity accumulates, provides further evidence of the complex's in vivo stability.

[0110] A challenging aspect of developing theranostic ligands is the need to balance optimal pharmacokinetics for imaging, such as rapid tissue distribution and clearance from the blood, while maintaining progression and sustained tumor loading, and simultaneously achieving optimal therapeutic characteristics, such as clearance from normal tissue. This challenge has been previously described for low molecular weight ligands. 64 This is evident in the pharmacokinetics of Cu-labeled PSMA inhibitors. Phosphoramidate ligands with rapid clearance from the blood and kidneys also show low uptake in LNCaP xenograft tumors, with washout almost complete by 48-hour pi, a trend also observed with urea-based ligands in PC3-PIP xenograft tumors. This latter ligand family is best suited for PET imaging at later time points. 64Cu]Cu-RPS-085 exhibits excellent imaging characteristics even at early time points, including high tumor uptake and rapid clearance from background, resulting in a high tumor-to-background ratio up to 4 hours pi. Furthermore, since the radioactivity in the tumor remains stable for a long period, up to 48 hours pi, imaging at later time points, i.e., 24 hours, can be performed to explore increased contrast against the background without increasing the patient's radiation exposure. Such concepts have already been established. 64 [Cu]Cu-PSMA-617 has been clinically validated, enabling the acquisition of high-quality PET images beyond 17 hours after injection.

[0111] A second challenging aspect of small molecule ligand design is the inability to accurately and comprehensively predict the complete impact of structural changes on compound pharmacokinetics. Previously, the inventors and others demonstrated that altering the lengths of the linker conjugating the PSMA-binding group, the metal chelate moiety, and the albumin-binding group affects both tumor uptake and retention, as well as renal clearance and retention. In addition, different albumin-binding groups on the fixed linker structure also profoundly affect clearance from the blood. Here, the applicants demonstrate that even when the chelating agent is not expected to contribute to either PSMA binding or albumin binding, alterations to the metal chelate moiety on the fixed structural platform also affect the ligand's pharmacokinetics. This finding has recently been described in smaller molecular scaffolds. The chelating agent appears to be responsible for a tenfold reduction in affinity to PSMA compared to DOTA-containing analogs. Furthermore, Cu 2+ -MeCOSar complex, +2, and Lu 3+ The overall charge of the -p-SCN-Bn-DOTA complex, -1, is different. Without being constrained by theory, this change in charge distribution may be involved in changes in the cooperativity of binding to these protein targets and in promoting changes in the compound's pharmacokinetics, particularly in renal clearance and retention.

[0112] The affinity for serum albumin, and therefore the radioactivity in the blood, was lower than predicted based on the structural similarities of RPS-085 to its previously reported homologous ligands. Consequently, no tumor loading progressing over time was observed. However, [ 67 Cu]Cu-RPS-085 was not significantly eliminated from the tumor over 24 hours, resulting in high accumulated radioactivity (A). Desorption from the tumor was evident up to 96 hours pi, with A at 699 (%ID / g)·hour. In parallel, clearance from the kidney was rapid. The accumulated radioactivity for the same time interval was 538 (%ID / g)·hour (Figure 6). Without being constrained by theory, this is likely due to both accelerated plasma clearance and a small reduction in affinity for PSMA compared to other trifunctional ligands. By comparison, [ 177 Lu]Lu-RPS-063 achieves substantially higher tumor integration of 1782 (%ID / g)·hours in the same animal model. However, this is accompanied by an A in the kidney of 4720 (%ID / g)·hours (Figure 6). These pharmacokinetics are reflected in the dose absorbed by the tumor and kidney. Over a period of 192 hours, the dose absorbed by the tumor was [ 67 For Cu]Cu-RPS-085, the dose absorbed by the kidneys is approximately 16 times greater, 177 It is 6.5 times larger than Lu]Lu-RPS-063. Furthermore, [ 67 The rapid clearance of Cu]Cu-RPS-085 is, 177 Compared to Lu]Lu-RPS-063, it results in a one-fifth reduction in the dose absorbed throughout the body. The applicants previously reported that it accumulates in LNCaP tumors. 177 Radioactivity of Lu]Lu-PSMA-617, A 腫瘍 The value was 544 (%ID / g)·hours over 96 hours, and the radioactivity A in the kidneys was 腎臓 It was determined that within the same window it was 260(%ID / g)·hours

[31] . 67 Cu]Cu-RPS-085 A 腫瘍 / A 腎臓 The ratio 1.3 is [177 Lu] Slightly lower than the ratio of PSMA-617, which is 2.1, A 腫瘍 It is 1.3 times larger. Therefore, [ 67 The therapeutic range of Cu]Cu-RPS-085 is [ 177 The therapeutic range of Lu]Lu-PSMA-617 is equivalent, 177 It could be much larger than Lu]Lu-RPS-063.

[0113] RPS-085 has promising characteristics as a potential ligand for radioligand therapy, but further benefits can be achieved by extending its plasma half-life. This approach is [ 64 It has recently been used to develop Cu]Cu-PSMA-ALB-89, and this [ 64 Cu]Cu-PSMA-ALB-89 has demonstrated progressive accumulation in xenograft tumors over 24 hours. However, high renal radioactivity and significant accumulation of radioactivity in the liver may hinder the conversion of this compound to RPS-085. The applicants recently explored an extended polyethylene glycol (PEG) linker as a way to modulate plasma pharmacokinetics, achieving accelerated renal clearance while maintaining tumor radioactivity. Incorporation of a bifunctionalized MeCOSar chelating agent into this molecular scaffold may further increase the dose delivered to the tumor.

[0114] Many PSMA-targeted ligands have been reported to be taken up by the salivary and lacrimal glands, and β - The toxicity of these structures, particularly due to the release of α-particles, limits the dose. Due to the small size of the salivary and lacrimal glands in mice, it is difficult to quantify the absorbed dose by imaging or biological distribution experiments. Therefore, the [ 67 It is not possible to quickly predict the possible toxicity of Cu]Cu-RPS-085. However, the β released by copper-67 - Since the particles are at an intermediate energy (141 keV), the predicted absorbed dose to normal tissue is similar to that of lutetium-177 and lower than that of iodine-131. 67Cu]Cu-RPS-085 is, in the same xenograft mouse model, [ 177 It is eliminated from normal tissue at a rate similar to that of Lu]Lu-PSMA-617. Therefore, toxicity to the salivary glands is at least that currently under clinical investigation. 177 I expect it won't be any worse than Lu-labeled PSMA ligand.

[0115] While certain embodiments are illustrated and described, those skilled in the art, after reading the foregoing specification, can perform modifications, substitutions of equivalents, and other types of alterations to the compounds or salts thereof, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers, or racemic mixtures of the art of the present invention as described herein. Each of the embodiments described above may also include or incorporate any or all of the disclosed variations or embodiments with respect to other embodiments and embodiments.

[0116] The art of the present invention is not limited to the specific embodiments described herein, and these embodiments are intended to be single examples of individual embodiments of the art of the present invention. Many modifications and variations of the art of the present invention can be made without departing from the spirit and scope, as will be obvious to those skilled in the art. In addition to those enumerated herein, functionally equivalent methods within the scope of the art of the present invention will be obvious to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. It should be understood that the art of the present invention is not limited to any particular method, reagent, compound, composition, labeled compound or biological system, and is naturally subject to change. It should also be understood that the terms used herein are for the purpose of describing only specific embodiments and are not intended to limit them. Thus, the breadth, scope and spirit of the art of the present invention are indicated solely by the appended claims, the definitions therein and any equivalents thereof, and the specification is intended to be considered merely illustrative.

[0117] The embodiments described herein as exemplary can be adequately implemented without any elements or limitations not specifically disclosed herein. Therefore, terms such as “comprising,” “including,” and “containing” should be interpreted broadly and without limitation. Furthermore, the terms and expressions used herein are used as descriptive expressions, not as limitations, and in using such terms and expressions, there is no intention to exclude any equivalents or parts thereof of the features shown and described, and it is recognized that various modifications are possible within the scope of the claimed technology. Furthermore, the phrase “essentially consisting of” is considered to include elements such as those specifically enumerated and additional elements that do not materially affect the fundamental and novel features of the claimed technology. The phrase “consisting of” excludes any unspecified elements.

[0118] In addition, where any feature or aspect of this disclosure is described in relation to the Markush group, a person skilled in the art will recognize that this disclosure also describes any individual member or subgroup of any member of the Markush group. Each of the narrower species and lower groupings falls within the scope of the general disclosure and forms part of the invention. This includes the general description of the invention with the condition or negative limitation that any subject matter is excluded from this species, regardless of whether the excluded matters are specifically enumerated herein.

[0119] As will be understood by those skilled in the art, for any and all purposes, in particular in terms of providing written explanations, all scopes disclosed herein also encompass any and all possible subranges and combinations thereof. It is sufficiently described, and readily apparent, that any enumerated scope can be subdivided into at least two, three, four, five, ten, and so on. As a non-restrictive example, each scope discussed herein can easily be subdivided into the lower third, the middle third, the upper third, and so on. Also, as will be understood by those skilled in the art, all language such as “up to,” “at least,” “greater than,” and “less than” includes the enumerated numbers and refers to scopes that can be subdivided into subranges as discussed above. Finally, as will be understood by those skilled in the art, each scope includes its individual members.

[0120] All publications, patent applications, granted patents, and other documents (e.g., academic journals, articles, and / or textbooks) referenced herein are incorporated by reference in such a manner as each individual publication, patent application, granted patent, or other document is specifically and individually indicated as if it were incorporated holistically by reference. Definitions contained in the texts incorporated by reference are excluded to the extent that they conflict with the definitions in this disclosure. The technology of the present invention may include, but is not limited to, the features and combinations of features listed in the following items, and it should be understood that these items should not be construed as limiting the scope of the claims accompanying this specification or requiring all such features to be included in such claims:

[0121] A. A tumor targeting domain comprising a portion capable of recognizing or interacting with molecular targets on the surface of tumor cells, Blood protein binding domain and Sarcofazine-containing domain and A compound comprising the above, wherein the tumor targeting domain is located distal to the blood protein binding domain and is not sterically hindered by the blood protein binding domain.

[0122] B. The compound described in item A, wherein the tumor-targeting domain binds to one or more tumor-related molecular targets selected from tumor-specific cell surface proteins, prostate-specific membrane antigen (PSMA), somatostatin peptide receptor-2 (SSTR2), alpha v beta 3 (αvβ3), alpha v beta 6, gastrin-releasing peptide receptor, seplase, fibroblast-activating protein alpha (FAP-alpha), incretin receptor, glucose-dependent insulin-secreting polypeptide receptor, VIP-1, NPY, folate receptor, LHRH, neuron transporter (e.g., norepinephrine transporter (NET)), EGFR, HER-2, VGFR, MUC-1, CEA, MUC-4, ED2, TF antigen, endothelium-specific marker, neuropeptide Y, uPAR, TAG-72, claudin, CCK analog, VIP, bombesin, VEGFR, tumor-specific cell surface proteins, GLP-1, CXCR4, hepsin, TMPRSS2, caspace, cMET, or overexpressed peptide receptors. C. Compounds described in item A or item B, wherein the tumor targeting domain includes a modified antibody, a modified antibody fragment, a modified binding peptide, a prostate-specific membrane antigen ("PSMA") binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seplasin binding compound, or one or more binding fragments thereof.

[0123] D. Tumor targeting domains include belimumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasdotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, siltuximab, and A compound listed in any one of items A to C, including miprimab, nivolumab, pembrolizumab, olaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-Afrivercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, cyclostumumab, girentuximab, nimotuzumab, catumakisomab, or etalacizumab. E. Tumor targeting domains include belimumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasdotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, siltuximab, semiprima A compound listed in any one of items A to C, containing an antigen-binding fragment of nivolumab, pembrolizumab, olaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-Afrivercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, cyclostumumab, girentuximab, nimotuzumab, catumakisomab, or etalacizumab.

[0124] F. A compound according to any one of items A to E, wherein the compound is one of formulas I to V, or a pharmaceutically acceptable salt and / or solvate thereof. [ka] (In the formula, TTD is a tumor targeting domain, BBD is a blood protein binding domain, Sarc is a sarcofadin-containing domain, X 1 In each occurrence, independently, the non-existent O, S, NH, -C(O)-, and -C(O)-NR exist. 1 -, -NR 2 -C(O)-, -C(O)-NR 3 -C1-C 12 Alkylene-,-C1-C 12 Alkylene-C(O)-,-C(O)-NR 4 -C1-C 12 Alkylene-C(O)-, -arylene-, -heterocyclene-, -O(CH2CH2O) a -,-CH2CH2-O(CH2CH2O) b -,-CH2CH2-O(CH2CH2O) c -CH2CH2-, -O(CH2CH2O) d -CH2CH2-, -C(O)-O(CH2CH2O) e -, -O(CH2CH2O) f -CH2CH2C(O)-,-C(O)-O(CH2CH2O) g -, -C(O)-O(CH2CH2O) h -CH2CH2-, -C(O)-O(CH2CH2O) i -CH2CH2C(O)-, -CH2CH2-O(CH2CH2O) j -CH2CH2C(O)-, -C(O)-NR 5 -CH2CH2O(CH2CH2O) k -, -C(O)-NR 6 -CH2CH2O(CH2CH2O) l -CH2CH2-, -C(O)-NR 7 -CH2CH2O(CH2CH2O) m-CH2CH2C(O)-, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any combination of two or more thereof, where a, b, c, d, e, f, g, h, i, j, k, l, and m are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 in each occurrence, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In each occurrence, independently, it is H, alkyl, or aryl. L 1 In each occurrence, independently, the non-existent O, S, NH, -C(O)-, and -C(O)-NR exist. 8 -, -NR 9 -C(O)-, -C(O)-NR 10 -C1-C 12 Alkylene-,-C1-C 12 Alkylene-C(O)-,-C(O)-NR 11 -C1-C 12 Alkylene-C(O)-, -arylene-, -heterocyclene-, -O(CH2CH2O) a’ -,-CH2CH2-O(CH2CH2O) b’ -,-CH2CH2-O(CH2CH2O) c’ -CH2CH2-, -O(CH2CH2O) d’ -CH2CH2-, -C(O)-O(CH2CH2O) e’ -, -O(CH2CH2O) f’ -CH2CH2C(O)-, -C(O)-O(CH2CH2O) g’ -, -C(O)-O(CH2CH2O) h’ -CH2CH2-, -C(O)-O(CH2CH2O) i’ -CH2CH2C(O)-, -CH2CH2-O(CH2CH2O) j’ -CH2CH2C(O)-, -C(O)-NR 12 -CH2CH2O(CH2CH2O) k’ -, -C(O)-NR 13-CH2CH2O(CH2CH2O) l’ -CH2CH2-, -C(O)-NR 14 -CH2CH2O(CH2CH2O) m’ -CH2CH2C(O)-, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any combination of two or more thereof, where a', b', c', d', e', f', g', h', i', j', k', l', and m' are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 in each occurrence, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 In each occurrence, independently, it is H, alkyl, or aryl. L 2 In each occurrence, independently, the non-existent O, S, NH, -C(O)-, and -C(O)-NR exist. 15 -, -NR 16 -C(O)-, -C(O)-NR 17 -C1-C 12 Alkylene-,-C1-C 12 Alkylene-C(O)-,-C(O)-NR 18 -C1-C 12 Alkylene-C(O)-, -arylene-, -heterocyclene-, -O(CH2CH2O) a’’ -,-CH2CH2-O(CH2CH2O) b’’ -,-CH2CH2-O(CH2CH2O) c’’ -CH2CH2-, -O(CH2CH2O) d’’ -CH2CH2-, -C(O)-O(CH2CH2O) e’’ -, -O(CH2CH2O) f’’ -CH2CH2C(O)-, -C(O)-O(CH2CH2O) g’’ -, -C(O)-O(CH2CH2O) h’’ -CH2CH2-, -C(O)-O(CH2CH2O) i’’ -CH2CH2C(O)-, -CH2CH2-O(CH2CH2O) j’’-CH2CH2C(O)-, -C(O)-NR 19 -CH2CH2O(CH2CH2O) k’’ -, -C(O)-NR 20 -CH2CH2O(CH2CH2O) l’’ -CH2CH2-, -C(O)-NR 21 -CH2CH2O(CH2CH2O) m’’ -CH2CH2C(O)-, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any combination of two or more thereof, where a'', b'', c'', d'', e'', f'', g'', h'', i'', j'', k'', l'', and m'' are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 in each occurrence, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 In each occurrence, independently, it is H, alkyl, or aryl. p is independently 0, 1, 2, 3, 4, or 5 in each occurrence. (q is either 1 or 2 in each occurrence.)

[0125] G. The tumor targeting domain [ka] (In the ceremony W 1 , W 2 , W 3 , and W 4 These are -C(O)- and -(CH2) respectively, independently. r -, or -(CH2) s It is -NH-C(O)-, r is independently 1 or 2 in each occurrence. s is independently 1 or 2 in each occurrence. P 1 , P 2 , P 3 , P 4, P 5 , P 6 , P 7 , P 8 , P 9 , P 10 , P 11 , and P 12 These are, independently, H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl, (o, o', and o'' are each independently either 0 or 1.) A compound listed in any one of items A to F.

[0126] HP 1 , P 2 , P 3 , P 4 , P 5 , P 6 , P 7 , P 8 , P 9 , P 10 , P 11 , and P 12 However, each is independently H or tert-butyl, as described in item G. IP 1 , P 2 , P 3 , P 4 , P 5 , P 6 , P 7 , P 8 , P 9 , P 10 , P 11 , and P 12 However, each is independently H, and is a compound as described in item G or item H.

[0127] J. The blood protein binding domain [ka] (In the formula, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 In each occurrence, independently, it is H, halo, or alkyl. X2 and X 3 Each is independently either O or S, t is independently 0, 1, or 2 in each occurrence. u is either 0 or 1 independently in each occurrence. v is either 0 or 1 independently in each occurrence. w is independently 0, 1, 2, 3, or 4 in each occurrence, and u and v cannot be the same value. A compound listed in any one of items A to I.

[0128] K. A compound described in any one of items A to I, wherein the blood protein binding domain contains myristic acid, substituted or unsubstituted indole-2-carboxylic acid, substituted or unsubstituted thioamide, substituted or unsubstituted 4-oxo-4-(5,6,7,8-tetrahydronaphthalene-2-yl)butanoic acid, substituted or unsubstituted naphthalene acylsulfonamide, substituted or unsubstituted diphenylcyclohexanol phosphate ester, substituted or unsubstituted 4-iodophenylalkanoic acid, substituted or unsubstituted 3-(4-iodophenyl)propionic acid, substituted or unsubstituted 2-(4-iodophenyl)acetic acid, or substituted or unsubstituted 4-(4-iodophenyl)butanoic acid.

[0129] L. The blood protein binding domain [ka] A compound listed in any one of items A to I.

[0130] The M. sarcofadin-containing domain [ka] (In the formula, R 22 is H, alkyl, aryl, or NR 23 R 24 And, R 23 and R 24Each of these is independently H, alkyl, aryl, alkanoyl, or aryloyl, L 3 -C(O)-, -C1-C does not exist. 12 Alkylene-,-C1-C 12 Alkylene-C(O)-,-NR 25 C(O)-C1-C 12 Alkylene-C(O)-,-C1-C 12 Alkilen-NR 25 C(O)-C1-C 12 Alkylene-C(O)-, -Arirene-, -C1-C 12 Alkylene-C(O)NR 25 -CH2-phenylene-CH2-,-C1-C 12 Alkylene-C(O)NR 25 -CH2-phenylene-C(O)-, -C1-C 12 Alkilen-NR 25 C(O)-C1-C 12 Alkylene-C(O)-C(O)NR 25 -CH2-phenylene-CH2-, or -C1-C 12 Alkilen-NR 25 C(O)-C1-C 12 Alkylene-C(O)-C(O)NR 25 It is -CH2-phenylene-C(O)-, R 25 (Each instance is independently H, alkyl, or aryl.) A compound listed in any one of items A to L.

[0131] NR 22 A compound as described in item M, wherein the compound is H, methyl, or NH2. O. The sarcofadin-containing domain 64 Cu +2 or 67 Cu +2 A compound listed in any one of items A to N that chelates the compound. A composition comprising a compound described in any one of items A to O on page P, and a pharmaceutically acceptable carrier. Q. An effective amount of the compound described in item O for imaging and / or detecting one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumor, pituitary tumor, vasoactive enteropeptide-secreting tumor, glioma, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer. Pharmacologically acceptable carriers and A pharmaceutical composition containing the above.

[0132] R. A pharmaceutical composition as described in item Q, formulated for intravenous administration and optionally containing sterile water, Ringer's solution, or isotonic aqueous physiological saline. S. A pharmaceutical composition according to item Q or item R, wherein the effective amount of the compound is approximately 0.01 μg to approximately 10 mg of the compound per gram of the pharmaceutical composition. T. A pharmaceutical composition according to any one of items Q to S, wherein the pharmaceutical composition is provided in an injectable dosage form. U. A step of administering an effective amount of the compound described in item O for imaging and / or detecting cancer, The steps include detecting one or more of the following after administration: positron emission, gamma rays from positron emission and annihilation, and Cherenkov rays from positron emission. Methods that include...

[0133] V. The method according to item U, wherein the cancer includes one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumor, pituitary tumor, vasoactive enteropeptide-secreting tumor, glioma, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer. W. The method described in item U or item V, for subjects suspected of having mammalian tissue overexpressing prostate-specific membrane antigen ("PSMA"). X. The method according to any one of items U to W, wherein the mammalian tissue comprises one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumor, pituitary tumor, vasoactive enteropeptide-secreting tumor, glioma, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer.

[0134] Y. The method according to item X, wherein the step of administering the compound includes parenteral administration or intravenous administration. Z. An effective amount of the compound described in item O for treating one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer, Pharmacologically acceptable carriers and A pharmaceutical composition containing the above.

[0135] AA. A pharmaceutical composition as described in item Z, formulated for intravenous administration and optionally containing sterile water, Ringer's solution, or isotonic aqueous physiological saline. AB. A pharmaceutical composition according to item Z or item AA, wherein the effective amount of the compound is approximately 0.01 μg to approximately 10 mg per gram of the pharmaceutical composition. AC. A pharmaceutical composition according to any one of items Z to AB, wherein the pharmaceutical composition is provided in an injectable dosage form.

[0136] AD. Effective amounts of compounds for treating one or more of the following cancers: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumors, pituitary tumors, vasoactive enteropeptide-secreting tumors, gliomas, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancers. A pharmaceutical composition according to any one of items Z to AC, which is an effective amount of a compound for imaging and / or detecting one or more of the following: bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumor, pituitary tumor, vasoactive intestinal peptide secreting tumor, glioma, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer.

[0137] A method comprising the step of administering an effective amount of a compound listed in item O for the treatment of cancer. The method according to item AE, wherein the cancer includes one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumor, pituitary tumor, vasoactive enteropeptide-secreting tumor, glioma, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer. The method according to item AE or item AF, wherein the step of administering the compound AG includes parenteral administration.

[0138] AH. The method according to any one of items AE to AG, wherein the step of administering the compound includes intravenous administration. AI. The method according to any one of items AE to AH, wherein the effective amount of a compound for treating cancer is approximately 0.1 μg to approximately 50 μg per kilogram of body weight of the subject. AJ. The method according to any one of items AE-AI, wherein the effective amount of the compound is also the effective amount of the compound for imaging and / or detecting cancer. Along with the full scope of equivalents for which such claims are protected, other embodiments are described in the following claims.

Claims

1. A compound of formula (IV) or formula (V) or a pharmaceutically acceptable salt and / or solvate thereof: (In the formula, TTD is the tumor targeting domain, BBD is a blood protein binding domain, Sarc is a sarcofadin-containing domain, X 2 , 2 , 2 , e , 2 , 2 , 2 , 2 , g , i , b , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , c , 2 , 2 , 2 , 2 , 2 , d , 2 , 2 , f , h , 2 , 2 , 2 , 2 is, independently at each occurrence, absent, O, S, NH, -C(O)-, -C(O)-NR 1 -, -NR 2 -C(O)-, -C(O)-NR 3 -C 1 -C 12 alkylene-, -C 1 -C<​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​-O(CH 2 CH 2 O) j -CH 2 CH 2 C(O)-, -C(O)-NR 5 -CH 2 CH 2 O(CH 2 CH 2 O) k -, -C(O)-NR 6 -CH 2 CH 2 O(CH 2 CH 2 O) l -CH 2 CH 2 -, -C(O)-NR 7 -CH 2 CH 2 O(CH 2 CH 2 O) m -CH 2 CH 2 C(O)-, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any combination of two or more thereof, where a, b, c, d, e, f, g, h, i, j, k, l, and m are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 in each occurrence, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 In each occurrence, independently, it is H, alkyl, or aryl. L 1 is, independently at each occurrence, absent, O, S, NH, -C(O)-, -C(O)-NR 8 -, -NR 9 -, -C(O)-, -C(O)-NR 10 -C 1 -C 12 alkylene-, -C 1 -C 12 alkylene-C(O)-, -C(O)-NR 11 -C 1 -C 12 alkylene-C(O)-, -arylene-, -heterocyclene-, -O(CH 2 CH 2 O) a’ -, -CH 2 CH 2 -O(CH 2 CH 2 O) b’ -, -CH 2 CH 2 -O(CH 2 CH 2 O) c’ -CH 2 CH 2 -, -O(CH 2 CH<� 2 O) d’ -CH 2 CH 2 -, -C(O)-O(CH 2 CH 2 O) e’ -, -O(CH 2 CH 2 eO) f’ -CH 2 CH 2 C(O)-, -C(O)-O(CH 2 CH 2 O) g’ -, -C(O)-O(CH 2 CH 2 O) h’ -CH 2 CH 2 -, -C(O)-O(CH 2 CH 2 O)<� i’ -CH 2 CH 2 C(O)-, -CH 2 CH 2 -O(CH 2 CH 2 O) j’ -CH 2 CH 2 C(O)-, -C(O)-NR 12 -CH 2 CH 2 O(CH 2 CH 2 O) k’ -, -C(O)-NR 13 -CH 2 CH 2 O(CH 2 CH 2 O) l’ -CH 2 CH 2 -, -C(O)-NR 14 -CH 2 CH 2 O(CH 2 CH 2 O) m’ -CH 2 CH 2 C(O)-, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any combination of two or more thereof, where a', b', c', d', e', f', g', h', i', j', k', l', and m' are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 in each occurrence, R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , and R 14 In each occurrence, independently, it is H, alkyl, or aryl. L 2 In each occurrence, independently, the non-existent O, S, NH, -C(O)-, -C(O)-NR 15 -, -NR 16 -C(O)-, -C(O)-NR 17 -C 1 -C 12 Alkylene-, -C 1 -C 12 Alkylene-C(O)-,-C(O)-NR 18 -C 1 -C 12 Alkylene-C(O)-, -Arirene-, -Heterocyclene-, -O(CH) 2 CH 2 O) a’’ -ien-CH 2 CH 2 -O(CH 2 CH 2 O) b’’ -ien-CH 2 CH 2 -O(CH 2 CH 2 O) c’’ -CH 2 CH 2 -, -O(CH 2 CH 2 O) d’’ -CH 2 CH 2 -, -C(O)-O(CH 2 CH 2 O) e’’ -, -O(CH 2 CH 2 O) f’’ -CH 2 CH 2 C(O)-, -C(O)-O(CH 2 CH 2 O) g’’ -, -C(O)-O(CH 2 CH 2 O) h’’ -CH 2 CH 2 -, -C(O)-O(CH 2 CH 2 O) i’’ -CH 2 CH 2 C(O)-, -CH 2 CH 2 -O(CH 2 CH 2 O) j’’ -CH 2 CH 2 C(O)-, -C(O)-NR 19 -CH 2 CH 2 O(CH 2 CH 2 O) k’’ -, -C(O)-NR 20 -CH 2 CH 2 O(CH 2 CH 2 O) l’’ -CH 2 CH 2 -, -C(O)-NR 21 -CH 2 CH 2 O(CH 2 CH 2 O) m’’ -CH 2 CH 2 C(O)-, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or any combination of two or more thereof, where a'', b'', c'', d'', e'', f'', g'', h'', i'', j'', k'', l'', and m'' are independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19 in each occurrence, R 15 , R 16 , R 17 , R 18 , R 19 , R 20 , and R 21 In each occurrence, independently, it is H, alkyl, or aryl. p is independently 0, 1, 2, 3, 4, or 5 in each occurrence. q is either 1 or 2 in each occurrence.

2. The tumor targeting domain targets tumor-specific cell surface proteins, prostate-specific membrane antigen (PSMA), somatostatin peptide receptor-2 (SSTR2), alpha-v-beta-3 (αvβ3), alpha-v-beta-6, gastrin-releasing peptide receptor, seplase, fibroblast-activating protein alpha (FAP-alpha), incretin receptor, glucose-dependent insulin-secreting polypeptide receptor, VIP-1, NPY, folate receptor, LHRH, and neuronal transporters (e.g., noradrenaline transporter). The compound according to claim 1, which binds to a tumor-associated molecular target selected from one or more of the following: a neurotransmitter (NET), EGFR, HER-2, VGFR, MUC-1, CEA, MUC-4, ED2, TF antigen, endothelial-specific marker, neuropeptide Y, uPAR, TAG-72, claudin, CCK analog, VIP, bombesin, VEGFR, tumor-specific cell surface protein, GLP-1, CXCR4, hepsin, TMPRSS2, casspace, cMET, or an overexpressed peptide receptor.

3. The compound according to claim 1 or 2, wherein the tumor targeting domain comprises a modified antibody, a modified antibody fragment, a modified binding peptide, a prostate-specific membrane antigen ("PSMA") binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seplasin binding compound, or one or more binding fragments thereof.

4. The tumor targeting domain is belimumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasdotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, siltuximab, semip A compound according to any one of claims 1 to 3, comprising limab, nivolumab, pembrolizumab, olaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-Afrivercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, cyclostumumab, girentuximab, nimotuzumab, catumakisomab, or etalacizumab.

5. The tumor targeting domains are belimumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasdotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, siltuximab, and semiprimab. A compound according to any one of claims 1 to 3, comprising an antigen-binding fragment of nivolumab, pembrolizumab, olaratumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-Afrivercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, cyclostumumab, girentuximab, nimotuzumab, catumakisomab, or etalacizumab.

6. The tumor targeting domain, , (In the formula, W 1 , W 2 , W 3 , and W 4 These are, independently, -C(O)- and -(CH 2 ) r - or - (CH 2 ) s -NH-C(O)-, r is independently 1 or 2 in each occurrence. s is independently 1 or 2 in each occurrence. P 1 , P 2 , P 3 , P 4 , P 5 , P 6 , P 7 , P 8 , P 9 , P 10 , P 11 , and P 12 These are, independently, H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl. (o, o', and o'' are each independently either 0 or 1.) The compound according to any one of claims 1 to 5.

7. P 1 , P 2 , P 3 , P 4 , P 5 , P 6 , P 7 , P 8 , P 9 , P 10 , P 11 , and P 12 The compound according to claim 6, wherein each is independently H or tert-butyl.

8. P 1 , P 2 , P 3 , P 4 , P 5 , P 6 , P 7 , P 8 , P 9 , P 10 , P 11 , and P 12 The compound according to claim 6 or 7, wherein each is independently H.

9. The blood protein binding domain, 【Transformation 3】 (In the formula, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 In each occurrence, independently, it is H, halo, or alkyl. X 2 and X 3 These are, independently, O or S, t is independently 0, 1, or 2 in each occurrence. u is either 0 or 1 independently in each occurrence. v is independently 0 or 1 in each occurrence. w is independently 0, 1, 2, 3, or 4 in each occurrence, and u and v cannot be the same value. The compound according to any one of claims 1 to 8.

10. The compound according to any one of claims 1 to 8, wherein the blood protein binding domain comprises myristic acid, substituted or unsubstituted indole-2-carboxylic acid, substituted or unsubstituted thioamide, substituted or unsubstituted 4-oxo-4-(5,6,7,8-tetrahydronaphthalene-2-yl)butanoic acid, substituted or unsubstituted naphthalene acylsulfonamide, substituted or unsubstituted diphenylcyclohexanol phosphate ester, substituted or unsubstituted 4-iodophenylalkanoic acid, substituted or unsubstituted 3-(4-iodophenyl)propionic acid, substituted or unsubstituted 2-(4-iodophenyl)acetic acid, or substituted or unsubstituted 4-(4-iodophenyl)butanoic acid.

11. The blood protein binding domain, 【Chemistry 4】 The compound according to any one of claims 1 to 8.

12. The sarcofadin-containing domain, 【Transformation 5】 (In the ceremony R 22 is H, alkyl, aryl, or NR 23 R 24 And, R 23 and R 24 Each of these is independently H, alkyl, aryl, alkanoyl, or aryloyl, L 3 It does not exist, -C(O)-, -C 1 -C 12 Alkylene-, -C 1 -C 12 Alkylene-C(O)-,-NR 25 C(O)-C 1 -C 12 Alkylene-C(O)-, -C 1 -C 12 Alkylene-NR 25 C(O)-C 1 -C 12 Alkylene-C(O)-, -Arirene-, -C 1 -C 12 Alkylene-C(O)NR 25 -CH 2 -Phenylene-CH 2 -, -C 1 -C 12 Alkylene-C(O)NR 25 -CH 2 -Phenylene-C(O)-, -C 1 -C 12 Alkylene-NR 25 C(O)-C 1 -C 12 Alkylene-C(O)-C(O)NR 25 -CH 2 -Phenylene-CH 2 -, or -C 1 -C 12 Alkylene-NR 25 C(O)-C 1 -C 12 Alkylene-C(O)-C(O)NR 25 -CH 2 It is -phenylene-C(O)-, R 25 (Each instance is independently H, alkyl, or aryl.) The compound according to any one of claims 1 to 11.

13. R 22 is H, methyl, or NH 2 The compound according to claim 12.

14. Sarcofazine-containing domain 64 Cu +2 or 67 Cu +2 A compound according to any one of claims 1 to 13, which chelates the compound.

15. A composition comprising the compound described in any one of claims 1 to 14.

16. A pharmaceutical composition comprising an effective amount of the compound described in claim 14 for imaging and / or detecting one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumor, pituitary tumor, vasoactive enteropeptide-secreting tumor, glioma, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer.

17. A pharmaceutical composition comprising an effective amount of the compound described in claim 14 for use in a method for imaging and / or detecting cancer, wherein the method is The step of administering the aforementioned pharmaceutical composition to the target, The steps include detecting one or more of the following after administration: positron emission, gamma rays from positron emission and annihilation, and Cherenkov rays from positron emission. The pharmaceutical composition comprising the above.

18. The pharmaceutical composition according to claim 17, wherein the cancer comprises one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumor, pituitary tumor, vasoactive intestinal peptide secreting tumor, glioma, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer.

19. The pharmaceutical composition according to claim 17 or 18, wherein the subject is suspected to have mammalian tissue that overexpresses prostate-specific membrane antigen ("PSMA").

20. The pharmaceutical composition according to claim 19, wherein the mammalian tissue comprises one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumor, pituitary tumor, vasoactive enteropeptide-secreting tumor, glioma, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer.

21. The pharmaceutical composition according to claim 20, wherein the step of administering the pharmaceutical composition includes parenteral administration or intravenous administration.

22. A pharmaceutical composition comprising an effective amount of the compound described in claim 14 for treating one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumor, pituitary tumor, vasoactive intestinal peptide secreting tumor, glioma, breast cancer, adrenocortical cancer, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer.

23. A pharmaceutical composition comprising an effective amount of the compound described in claim 14 for the treatment of cancer.

24. The pharmaceutical composition according to claim 23, wherein the cancer comprises one or more of the following: non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, gallbladder cancer, pancreatic cancer, esophageal cancer, melanoma, liver cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, prostate cancer, neuroendocrine tumor, pituitary tumor, vasoactive intestinal peptide secreting tumor, glioma, breast cancer, adrenocortical carcinoma, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, and metastatic cancer.

25. The pharmaceutical composition according to claim 23 or 24, for parenteral or intravenous administration.

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