Ligands and their use

Abstract

The present disclosure provides 89 bound to a second chelating ligand selective for radionuclides other than Zr 89 The present disclosure relates to compounds containing a first chelating ligand selective for Zr. Also disclosed are complexes, pharmaceuticals, and compositions containing the compounds. The disclosure also provides methods for using and preparing the compounds, complexes, pharmaceuticals, and compositions.

Description

[Technical Field]

[0001] This disclosure relates to chelate ligands for one or more radionuclides with potential as pharmaceuticals, and to complexes of such radionuclides with such ligands. This disclosure also relates to pharmaceuticals, compositions, and kits comprising such ligands and complexes, as well as methods for use and manufacture. [Background technology]

[0002] In therapy and imaging, certain metals are becoming increasingly important, particularly in relation to neoplastic diseases. The metals of interest typically act either as contrast agents, improving the sensitivity of imaging techniques by emitting radiation through radioactive decay from within the body, or for therapeutic purposes.

[0003] For some imaging techniques, certain non-radioactive nuclides may also be useful. Radioactive nuclides used for imaging or therapy are selected based on various characteristics, including the type of radiation emitted by the isotope and the isotope's half-life.

[0004] For pharmaceutical use, radionuclides are typically formulated as complexes with organic ligands that coordinate or bind to them with high affinity, usually via chelation through four or more binding sites. This assistance in high affinity enhances the overall stability of the complex between the radionuclide and the polydentate ligand, reducing leaching of the radionuclide from the complex (loss of metal due to complex dissociation) or chelation (transfer of metal to a different ligand or molecule) during administration.

[0005] Despite their ability to form multiple binding interactions, not all chelateable ligands are suitable for binding to a given radionuclide for pharmaceutical use as a complex. Different ligands exhibit different affinities and selectivity for different radionuclides. Therefore, the appropriate ligand must be used in combination with the desired radionuclide.

[0006] For example, the radioactive nuclide zirconium-89 ( 89 There is growing interest in the pharmaceutical applications of Zr. 89 Zr (beta-positive emitter (av), 0.396 MeV) has potential for use in positron emission tomography (PET) imaging. 89 Zr is of particular interest in immunological PET (immuno-PET) imaging due to its long half-life of 3.3 days, which is comparable to the circulating half-life of antibodies. In immuno-PET imaging, tumors are imaged using radionuclide complexes that form conjugates with appropriate antibodies, based on the expression of tumor-associated antigens on tumor cells. However, immuno-PET imaging often suffers from the drawback of slow accumulation of radionuclide-antibody conjugates in target tissue. This is because, 89 This indicates that many radionuclides other than Zr that can be used in PET imaging methods do not have half-lives suitable for immuno-PET imaging.

[0007] A potential problem with the presence of different chelate ligands in a single compound or composition for complex formation with a given radionuclide is the possibility of competing ligand-radionuclide interactions. Competitive interactions between radionuclides and different chelate ligands indicate that the formation of multiple complexes (e.g., one complex between the radionuclide and one chelate ligand, and further complexes between the radionuclide and different chelate ligands) may be a concern, especially if the further complexes have intermediate affinity. Complexes with such intermediate affinity are prone to radionuclide leaching from the complex upon administration. In many cases, the concentration of such intermediate affinity complexes can be reduced to an appropriate level by carefully adjusting the stoichiometry and equilibrium time before administration. However, suitable administration for pharmaceutical use is difficult. The half-life of a radioactive nuclide indicates that the equilibrium time before administration should ideally be minimized.

[0008] There is a continuing need to develop ligands for radionuclides that may have pharmaceutical, diagnostic, and / or prognostic potential. 89Capable of chelating with Zr, preferably 89 There is also a need to develop pharmaceutically acceptable compounds that can selectively chelate with Zr or one or more further nuclides of therapeutic potential.

[0009] Reference to any prior art in this specification is not an acknowledgment or suggestion that this prior art forms part of the common general knowledge in any jurisdiction, or that this prior art is considered relevant by those skilled in the art, and / or that this prior art may reasonably be expected to be combined with other parts of the prior art. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEMS

[0010] In one aspect of the present invention, there is provided a compound, 89 comprising a first chelating ligand selective for Zr (chelating ligand 1), and 89 a second chelating ligand (chelating ligand 2) selective for nuclides of pharmaceutical potential other than Zr, wherein the first and second chelating ligands are covalently bonded by a linker group, the compound is provided.

[0011] In some embodiments, the compounds of the present invention are of Formula (I) [Chemical Formula] the compound of which is, A is 89 a chelating ligand selective for Zr, B is 89 a chelating ligand selective for nuclides of pharmaceutical potential other than Zr, L is a linker group.

[0012] In another aspect, of Formula (II) [ka] A compound of, Ch 1 It contains the radical of desferrioxamine B (DFOB), Ch 2 It contains the radical 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), L is a linker group. Provides compounds.

[0013] In further embodiments, the present invention provides a complex containing a compound and a metal. In some embodiments, the complex contains two different metals.

[0014] In further embodiments, the present invention provides a pharmaceutical product comprising the compound and a radionuclide with potential as a pharmaceutical. In some embodiments, the pharmaceutical product comprises the compound and two different radionuclides with potential as pharmaceuticals.

[0015] In a further embodiment, the present invention provides compositions comprising compounds, complexes, or pharmaceuticals and pharmaceutically acceptable excipients.

[0016] In a further embodiment, separate components, The present invention relates to compounds, complexes, pharmaceuticals, or compositions, and Instructions for using any of the methods of the present invention. including, We provide a kit of the components.

[0017] The present invention further relates to the use of such complexes, activators, compositions, and kits in the treatment, diagnosis, and / or prognosis of diseases. Accordingly, the compounds, complexes, therapeutic agents, or compositions of the present invention may be used in a variety of applications, such as therapeutic agents, diagnostic agents, or prognostic agents.

[0018] The present invention also provides a method for producing the compound, complex, pharmaceutical, or composition of the present invention.

[0019] All embodiments described herein should be considered to apply mutatis mutandis to any other embodiments unless otherwise specifically stated.

[0020] The scope of this disclosure is not limited by the specific embodiments described herein, which are intended for illustrative purposes only. Functionally equivalent products, compositions, and methods, as described herein, are clearly within the scope of the present invention.

[0021] Throughout this specification, unless otherwise specified or the context requires a different interpretation, a single step, composition, a group of steps, or a group of compositions in question shall be deemed to encompass one or more (i.e., one or more) of these steps, compositions, groups of steps, or groups of compositions in question.

[0022] definition Unless otherwise specified herein, the following terms shall be understood to have the general meanings to which they apply.

[0023] The term “C 1~6 "Alkyl" refers to a linear or branched hydrocarbon group having 1 to 6 carbon atoms that are optionally substituted. Examples include methyl (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr), butyl (Bu), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), pentyl, neopentyl, hexyl, and similar groups. Unless otherwise required by context, the term "C" is used. 1~6 "Alkyl" also includes alkyl groups that are bonded at two positions, i.e., divalent alkyl groups containing one less hydrogen atom. This includes methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. 1~4 "alkyl group" and "C 1~3 Alkyl alkyl groups are preferred, and methyl groups are particularly preferred.

[0024] The term “C2~6 "Alkenyl" refers to an optionally substituted linear or branched hydrocarbon group having at least one double bond in either E or Z stereochemistry and 2 to 6 carbon atoms, where applicable. Examples include vinyl, 1-propenyl, 1- and 2-butenyl, and 2-methyl-2-propenyl. Unless otherwise required by context, the term "C" is used. 2~6 "Alkenyl" also contains an alkenyl group that is two-positionally bonded, i.e., divalent, with one less hydrogen atom. "C" includes ethenyl, propenyl, and butenyl. 2~4 "Alkenil" and "C 2~3 Alkenyl is preferred, and ethenyl is particularly preferred.

[0025] The term “C 2~6 "Alkynyl" refers to an optionally substituted linear or branched hydrocarbon group having at least one triple bond and 2 to 6 carbon atoms. Examples include ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl and similar groups. Unless otherwise specified in the context, the term "C" is used. 2~6 "Alkynyl" also contains an alkynyl group that is bonded at two positions, i.e., a divalent alkynyl group with one less hydrogen atom. 2~3 Alkynyl is preferred.

[0026] The term “C 3~10 "Cycloalkyl" refers to a non-aromatic cyclic group having 3 to 10 carbon atoms, and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Cycloalkyl groups are understood to be saturated, like cyclohexyl, or unsaturated, like cyclohexenyl. C 3~6 Cycloalkyl groups are preferred. Cycloalkyl groups also include polycyclic carbocyclic groups, as well as condensed, crosslinked, and spirocyclic systems.

[0027] The terms "hydroxy" and "hydroxyl" refer to the group -OH.

[0028] The term "oxo" refers to the base element, which is oxygen (O).

[0029] The term “C 1~6 "Alkoxy" refers to the alkyl groups described above, such as methoxy, ethoxy, propoxy, isoproxy, butoxy, tert-butoxy, and pentoxy, which contain 1 to 6 carbon atoms and are covalently bonded via oxygen bonds. "C" includes methoxy, ethoxy, propoxy, and butoxy. 1~4 "alkoxy" and "C 1~3 Alkoxy is preferred, and methoxy is particularly preferred.

[0030] Term "HaroC" 1~6 "Alkyl" and "C 1~6 "Alkylhalo" refers to a C atom substituted with one or more halogens. 1~6 This refers to alkyl groups. For example, halo C groups such as -CH2CF3 and -CF3. 1~3 Alkyl is preferred.

[0031] Term "HaroC" 1~6 "alkoxy group" and "C 1~6 "Alkoxyhalo" refers to carbon ions substituted with one or more halogens. 1~6 This refers to alkoxy compounds. For example, C such as -OCF3. 1~3 Alkoxyhalos are preferred.

[0032] The term "carboxylic acid" or "carboxyl" refers to the group -COO- or -COOH.

[0033] The term "ester" refers to a group where the hydrogen atoms of the carboxyl group are separated, for example, C 1~6 Alkyl(carboxyl C) 1~6This refers to a carboxyl group substituted with an alkyl group (or alkyl ester), an aryl group, or an aralkyl group (or aralkyl ester). For example, methyl ester (CO2Me), ethyl ester (CO2Et), and propropyl ester. CO2C such as pyr esters (CO2Pr) 1~3 Alkyl alkyl groups are preferred, and their reverse esters (e.g., -OC(O)Me, -OC(O)Et, and -OC(O)Pr) are also included.

[0034] The terms "cyano" and "nitrile" refer to the group -CN.

[0035] The term "nitro" refers to the group -NO2.

[0036] The term "amino" refers to the group -NH2.

[0037] The term "substituted amino acid" refers to a molecule in which at least one hydrogen atom is replaced, for example, C. 1~6 Alkyl("C 1~6 This refers to an amino group that has been substituted with an alkylamino group, an aryl group, or an aralkyl group ("arylamino," "aralkylamino"). Substituted amino groups include monosubstituted amino (or secondary amino) groups, which have only one hydrogen atom, for example, C 1~6 This refers to an amino group substituted with an alkyl, aryl, or aralkyl group. Preferred secondary amino groups include, for example, methylamino (NHMe), ethylamino (NHEt), and propylamino (NHPr). 1~3 Alkylamino groups are included. Substituted amino groups also include "disubstituted amino" (or "tertiary amino") groups, which have two hydrogen atoms, for example, the same or different C 1~6 This refers to amino groups substituted with alkyl groups (dialkylamino), aryl groups, and alkyl groups ("aryl(alkyl)amino"). Preferred tertiary amino groups include, for example, dimethylamino (NMe2), diethylamino (NEt2), dipropylamino (NPr2), and their variants (e.g., N(Me)(Et)), such as di(C) 1~3Examples include alkyl(amino) groups.

[0038] The term "aldehyde" refers to the group -C(=O)H.

[0039] The terms "acyl" and "acetyl" refer to the group -C(O)CH3.

[0040] The term "ketone" refers to a carbonyl group that can be represented as -C(O)-.

[0041] The term "substituted ketone" refers to, for example, C 1~6 Alkyl("C 1~6 This refers to a ketone group covalently bonded to at least one additional group, such as an alkylacyl (alkyl ketone) or ketoalkyl (ketoalkyl), an aryl group (aryl ketone), or an aralkyl group (aralkyl ketone). 1~3 Alkylacyl groups are preferred.

[0042] The term "amide" refers to the group -C(O)NH2.

[0043] The term "substituted amide" refers to a material in which a hydrogen atom is replaced with, for example, C. 1~6 Alkyl("C 1~6 Alkylamide (C 1-6 "alkylamido)" or "C 1~6 Alkylamide (C 1-6 This refers to amide groups substituted with alkylamides, aryls ("arylamides"), aralkyl groups ("aralkylamides"), etc. For example, methylamide (-C(O)NHMe), ethylamide (-C(O)NHEt), and propylamide (-C(O)NHPr), etc. 1~3 Alkylamide groups are preferred, and their reverse amides (e.g., -NHMeC(O)-, -NHEtC(O)-, and -NHPrC(O)-) are also included.

[0044] The term "disubstituted amide" refers to a compound in which two hydrogen atoms of an amino group are replaced with, for example, C 1~6 Alkyl("di(C) 1~6 Alkylamide (di(C) 1-6 XML )amido) or "Ji (C 1~6 Alkylamide (di(C) 1-6 This refers to amide groups substituted with alkyl(aralkyl)amides, aralkyl and alkyl groups ("alkyl(aralkyl)amides"). For example, dimethylamide (-C(O)NMe2), diethylamide (-C(O)NEt2), and dipropylamide (-C(O)NPr2) and their variations (e.g., -C(O)N(Me)Et), di(C 1~3 Alkylamide groups are preferred, and their reverse amides are also included.

[0045] The term "thiol" refers to the group -SH.

[0046] The term “C 1~6 "Alkylthio" refers to the hydrogen atom of the thiol group being C 1~6 This refers to a thiol group substituted with an alkyl group. For example, thiomethyl, thioethyl, and thiopropyl, C 1~3 Alkylthio groups are preferred.

[0047] The term "thioxo" refers to the group = S.

[0048] The term "sulfinyl" refers to the group -S(=O)H.

[0049] The terms "substituted sulfinyl" or "sulfoxide" refer to a sulfinyl group where a hydrogen atom is replaced with, for example, C 1~6 Alkyl("C 1~6 "Alkyl sulfinyl" or "C 1~6This refers to a sulfinyl group substituted with alkyl sulfoxides, arylsulfinyls, aralkylsulfinyls, etc. For example, C-SO-methyl, -SO-ethyl, and -SO-propyl. 1~3 Alkyl sulfinyl groups are preferred.

[0050] The term "sulfonyl" refers to the group -SO2H.

[0051] The term "substituted sulfonyl" refers to a sulfonyl group where a hydrogen atom is replaced with, for example, C 1~6 Alkyl("Sulfonyl C") 1~6 This refers to sulfonyl groups substituted with alkyl, aryl ("aryl sulfonyl group"), aralkyl ("aralkyl sulfonyl"), etc. For example, sulfonyl C such as -SO2Me, -SO2Et, and -SO2Pr. 1~3 Alkyl alkyl groups are preferred.

[0052] The term "sulfonylamide" or "sulfonamide" refers to the group -SO2NH2.

[0053] The term "substituted sulfonamide" refers to a substance in which hydrogen is replaced with, for example, C 1~6 Alkyl("Sulfonylamide C") 1~6 This refers to sulfonamide groups substituted with alkyl groups, aryl groups ("aryl sulfonamides"), aralkyl groups ("aralkyl sulfonamides"), etc. For example, sulfonamides such as SO2NHMe, -SO2NHEt, and -SO2NHPr. 1~3 Alkyl groups are preferred, and their inverse sulfonamides (e.g., -NHSO2Me, -NHSO2Et, and -NHSO2Pr) are also included.

[0054] The term "disubstituted sufonamido" or "disubstituted sulphonamide" refers to a compound in which two hydrogen atoms of a sulfonylamide group are replaced with, for example, the same or different C atoms. 1~-6 Alkyl("Sulfonylamide di(C) 1~6 This refers to sulfonylamide groups substituted with alkyl groups, aralkyl groups, and alkyl groups ("sulfonamide (aralkyl)alkyl"). For example, sulfonylamide di(C) such as -SO2NMe2, -SO2NEt2, and -SO2NPr2 and their variations (e.g., -SO2N(Me)Et). 1~3 Alkyl groups are preferred, and these inverse sulfonamides (e.g., -N(Me)SO2Me) are preferred. This also includes (etc.).

[0055] The term "sulfuric acid" refers to the group OS(O)2OH, where the hydrogen atoms of the group are, for example, C 1~6 Contains groups substituted with alkyl groups (alkylsulfates), aryl groups (arylsulfates), aralkyl groups (aralkylsulfates), etc. For example, OS(O)2OMe, OS(O)2OEt, and OS(O)2OPr, etc. 1~3 Sulfuric acid is preferred.

[0056] The term "sulfonic acid" refers to the group SO3H, where the hydrogen atoms of the group are, for example, C 1~6 Includes groups substituted with alkyl groups ("alkylsulfonates"), aryl groups ("arylsulfonates"), aralkyl groups ("aralkylsulfonates"), etc. For example, C3Me, SO3Et, and SO3Pr. 1~3 Sulfonic acid is preferred.

[0057] The term "aryl" refers to a carbocyclic (not heterocyclic) aromatic ring or a monocyclic, bicyclic, or tricyclic ring system. Aromatic rings or ring systems generally consist of 6 to 10 carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, and tetrahydronaphthyl. Six-membered aryl rings such as phenyl are preferred. The term "aralkyl" refers to a C such as benzyl. 1~6 This refers to alkylaryl compounds.

[0058] The term "alkoxyaryl" refers to C13, such as benzyloxy. 1~6 This refers to alkyloxyaryl compounds.

[0059] The term "heterocyclyl" refers to a portion of a heterocyclic compound (unless otherwise specified) having 3 to 10 ring atoms, obtained by removing one hydrogen atom from one of the ring atoms, where 1, 2, 3, or 4 of the ring atoms are heteroatoms, and each heteroatom is independently selected from O, S, and N. Heterocyclyl groups include monocyclic and polycyclic (such as bicyclic) ring systems, including condensed, bridging, and spirocyclic systems, as long as at least one of the multiple rings in the ring system contains at least one heteroatom.

[0060] In this context, the prefixes 3-, 4-, 5-, 6-, 7-, 8-, 9-, and 10-membered rings indicate the number or range of ring atoms, whether carbon atoms or heteroatoms. For example, as used herein, the term "3- to 10-membered ring heterocyclyl" refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms. Examples of heterocyclyl groups include 5- to 6-membered ring monocyclic heterocyclyls and 9- to 10-membered ring fused bicyclic heterocyclyls.

[0061] Examples of monocyclic heterocyclyl groups include those containing one nitrogen atom, such as aziridine (3-membered ring), azetidine (4-membered ring), pyrrolidine (tetrahydropyrrole), pyrroline (e.g., 3-pyrrole, 2,5-dihydropyrrole), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole), or pyrrolidinone (5-membered ring), piperidine, dihydropyridine, tetrahydropyridine (6-membered ring), and azepine (7-membered ring), as well as imidazoline, pyrazolidine (diazolidine), imidazoline, Pyrazoline (dihydropyrazole) (5-membered ring), piperazine (6-membered ring) and other compounds containing two nitrogen atoms; oxirane (3-membered ring), oxetane (4-membered ring), oxolane (tetrahydrofuran), oxol (dihydrofuran) (5-membered ring), oxane (tetrahydropyran), dihydropyran, pyran (6-membered ring), oxepin (7-membered ring) and other compounds containing one oxygen atom; dioxolane (5-membered ring), dioxane (6-membered ring), and dioxepane (7-membered ring) and other compounds containing two oxygen atoms; trioxane (6-membered ring) and other compounds containing three oxygen atoms; thiirane (3-membered ring) Examples include, but are not limited to, those containing one sulfur atom, such as thiolane (tetrahydrothiophene) (5-membered ring), thiane (tetrahydrothiopyran) (6-membered ring), and thiepane (7-membered ring); those containing one nitrogen atom and one oxygen atom, such as tetrahydroxazole, dihydroxazole, tetrahydroisoxazole, dihydroisoxazole (5-membered ring), morpholine, tetrahydroxazine, dihydroxazine, and oxazine (6-membered ring); those containing one nitrogen atom and one sulfur atom, such as thiazoline, thiazolidinedione (5-membered ring), and thiomorpholine (6-membered ring); those containing two nitrogen atoms and one oxygen atom, such as oxadiazine (6-membered ring); those containing one oxygen atom and one sulfur atom, such as oxathiol (5-membered ring) and oxathiane (thioxane) (6-membered ring); and those containing one nitrogen atom, one oxygen atom, and one sulfur atom, such as oxathiazine (6-membered ring).

[0062] Heterocyclyls include aromatic heterocyclyls and non-aromatic heterocyclyls. Such groups may be substituted or unsubstituted.

[0063] The term "aromatic heterocyclyl" may be used interchangeably with the terms "heteroaromatic" or "heteroaryl" or "hetalil". The heteroatoms in the aromatic heterocyclyl group may be selected independently from N, S, and O. The aromatic heterocyclyl group may contain 1, 2, 3, 4 or more ring heteroatoms. In the case of a condensed aromatic heterocyclyl group, only one of the multiple rings may contain a heteroatom, and not all rings need to be aromatic.

[0064] As used herein, "heteroaryl" refers to an aromatic heterocyclic group and includes monocyclic aromatic ring systems and polycyclic (e.g., bicyclic) ring systems containing one or more aromatic rings. The term aromatic heterocyclil also includes pseudo-aromatic heterocyclils. The term "pseudo-aromatic" refers to a ring system that is not strictly aromatic but is stabilized by electron delocalization and behaves similarly to an aromatic ring. The term "aromatic heterocyclil" therefore also includes polycyclic ring systems in which all fused rings are aromatic rings and ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In polycyclic ring systems containing both fused aromatic and non-aromatic rings, this group can be bonded to another part by an aromatic ring or by a non-aromatic ring.

[0065] Examples of heteroaryl groups include monocyclic and bicyclic groups containing 5- to 10-membered rings. A heteroaryl group may be, for example, a monocyclic ring of 5 or 6 members, or a bicyclic structure formed from fused 5- and 6-membered rings, or two fused 6-membered rings or two fused 5-membered rings. Each ring may contain up to about 4 heteroatoms, typically selected from nitrogen, sulfur, and oxygen. A heteroaryl ring contains up to 4 heteroatoms, more commonly up to 3, more commonly up to 2, for example, just 1 heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms of the heteroaryl ring may be basic, as in the case of imidazole or pyridine, or intrinsically non-basic, as in the case of indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in a heteroaryl group containing any amino group substituent of the ring is less than 5.

[0066] The aromatic heterocyclyl group may be a monocyclic aromatic ring system with a 5-membered ring or a 6-membered ring.

[0067] Examples of five-membered monocyclic heteroaryl groups include furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (1,2,3 and 1,2,4 oxadiazolyl and furazanyl, i.e., 1,2,5-oxadiazolyl), thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, and triazolyl (1,2,3, 1,2,4 and 1 Examples include, but are not limited to, , 3,4 triazolyl, oxatriazolyl, tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyl), and similar compounds.

[0068] Examples of six-membered monocyclic heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyridadinyl, pyrazinyl, triazinyl, pyranyl, oxazinyl, dioxynyl, thiadinyl, thiadiazinyl, and similar groups. Examples of nitrogen-containing six-membered aromatic heterocyclyls include pyridyl (one nitrogen), pyrazinyl, pyrimidinyl, and pyridadinyl (two nitrogens).

[0069] The aromatic heterocyclyl group may also be a bicyclic or polycyclic heterocyclic aromatic ring system, such as a condensed ring system (purine, pteridinyl, naphthilidinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, and the like) or a bonded ring system (oligothiophene, polypyrrole, and the like). The condensed ring system may also include a five-membered or six-membered aromatic heterocyclyl condensed to a carbocyclic aromatic ring, such as phenyl, naphthyl, indenyl, azurenyl, fluorenyl, anthracenyl, and the like, for example, a five-membered aromatic heterocyclyl containing nitrogen condensed to a phenyl ring, or a five-membered aromatic heterocyclyl containing one or two nitrogens condensed to a phenyl ring.

[0070] Bicyclic heteroaryl groups include, for example, a) a benzene ring fused with a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, b) a pyridine ring fused with a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, c) a pyrimidine ring fused with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms, d) a pyrrole ring fused with a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, e) a pyrazole ring fused with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms, f) an imidazole ring fused with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms, g) an oxazole ring fused with a 5- or 6-membered ring containing 1 or 2 ring heteroatoms, h) 1 or The group may be selected from i) an isoxazole ring fused with a 5- or 6-membered ring containing two ring heteroatoms, j) an isothiazole ring fused with a 5- or 6-membered ring containing one or two ring heteroatoms, k) a thiophene ring fused with a 5- or 6-membered ring containing one, two, or three ring heteroatoms, I) a furan ring fused with a 5- or 6-membered ring containing one, two, or three ring heteroatoms, m) a cyclohexyl ring fused with a 5- or 6-membered ring containing one, two, or three ring heteroatoms, and n) a cyclopentyl ring fused with a 5- or 6-membered ring containing one, two, or three ring heteroatoms.

[0071] Specific examples of bicyclic heteroaryl groups containing a five-membered ring fused to another five-membered ring include, but are not limited to, imidazothiazole (e.g., imidazo[2,1-b]thiazole) and imidazoimidazole (e.g., imidazo[1,2-a]imidazole).

[0072] Specific examples of bicyclic heteroaryl groups containing a six-membered ring condensed onto a five-membered ring include, but are not limited to, benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, isobenzofuran, indole, isoindole, indidine, indoline, isoindoline, purines (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g., pyrazolo[1,5-a]pyrimidine), benzodioxole, and pyrazolopyridine (e.g., pyrazolo[1,5-a]pyridine) groups. Further examples of six-membered rings condensed onto a five-membered ring include pyrrolopyridine groups such as pyrrolo[2,3-b]pyridine.

[0073] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman, benzodioxane, quinoridine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, sinnoline, phthalazine, naphthyridine, and pteridine groups.

[0074] Examples of heteroaryl groups containing aromatic and non-aromatic rings include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydrobenzo[1,4]dioxin, benzo[1,3]dioxol, 4,5,6,7-tetrahydrobenzofuran, indoline, isoindoline, and indane groups.

[0075] Therefore, examples of aromatic heterocyclyls condensed on a carbocyclic aromatic ring include, but are not limited to, benzothiophenyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzoxazolyl, benzoisoxazolyl, isobenzoxazoyl, benzothiazolyl, benzoisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazinyl, phthalazinyl, carbolinyl, and similar compounds.

[0076] The term "non-aromatic heterocyclyl" encompasses optionally substituted saturated and unsaturated rings containing at least one heteroatom selected from the group consisting of N, S, and O. This ring may contain one, two, or three heteroatoms. It may be part of a monocyclic or polycyclic ring system. Polycyclic ring systems include fused rings and spiro rings. Not all rings in a non-aromatic heterocyclyl polycyclic ring system need to contain heteroatoms, provided that at least one ring contains one or more heteroatoms.

[0077] Non-aromatic heterocyclyls may be monocyclic rings with 3 to 7 members.

[0078] Examples of 5-membered non-aromatic heterocyclyl rings include 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrazolinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, imidazolidinyl, 3-dioxolanil, thiazolidinyl, isoxazolidinyl, 2-imidazolinyl, and similar rings.

[0079] Examples of six-membered non-aromatic heterocyclyl rings include piperidinyl, piperidinonyl, pyranyl, dihydropyranyl, tetrahydropyranyl, 2Hpyranyl, 4Hpyranyl, thianyl, thianyl oxide, thianyl dioxide, piperazinyl, diozanyl, 1,4-dioxynyl, 1,4-dithianyl, 1,3,5-triozalanyl, 1,3,5-trithianyl, 1,4-morpholinyl, thiomorpholinyl, 1,4-oxathianyl, triazinyl, 1,4-thiadinyl, and similar compounds.

[0080] Examples of seven-membered non-aromatic heterocyclyl rings include azepanyl, oxepanyl, thiepanyl, and similar rings.

[0081] Non-aromatic heterocyclyl rings may also be bicyclic heterocyclyl rings, such as bonded ring systems (e.g., uridinyl and similar) or fused ring systems. Fused ring systems include phenyl, naphthyl, indenyl, azlenyl, fluorenyl, anthracenyl and similar. This includes non-aromatic heterocyclyls with 5-membered, 6-membered, or 7-membered rings condensed onto a carbocyclic aromatic ring. Examples of non-aromatic heterocyclyls with 5-membered, 6-membered, or 7-membered rings condensed onto a carbocyclic aromatic ring include indolinyl, benzodiazepinyl, benzazepinyl, dihydrobenzofuranyl, and similar compounds.

[0082] The term "halo" refers to fluoro, chloro, bromo, or iodine.

[0083] Unless otherwise specified, the terms “optionally substituted” or “any substituent” as used herein mean C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkinyl, C 3-8 Cycloalkyl, hydroxyl, oxo, C 1-6 Alkoxy, aryloxy, C 1-6 Alkoxyaryl, Halo, C 1-6Haloalkyl (such as CF3), C 1-6 Haloalkoxy (such as OCF3), carboxyl, ester, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketone, substituted ketone, amide, aminoacyl, substituted amide, disubstituted amide, thiol, alkylthio, thioxo, sulfuric acid, sulfonic acid, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonylamide, substituted sulfonamide, disubstituted sulfonamide, aryl, arylC 1~6 alkyl, heterocyclyl and heteroaryl, which may be further unsubstituted or substituted with 1, 2, 3, 4 or more groups selected from the group consisting of, preferably 1, 2 or 3 groups, more preferably 1 or 2 groups, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heterocyclyl, as well as groups containing these, may optionally be further substituted. Any substituent in the case of N-containing heterocycles may also include C 1-6 alkyl, i.e., N-C 1-3 alkyl, more preferably methyl, especially N-methyl, but is not limited thereto.

[0084] For optionally substituted "C 1-6 alkyl", "C 2-6 alkenyl" and "C 2-6 alkynyl", the optional substituent or substituents are preferably selected from halo, aryl, heterocyclyl, C 3-8 cycloalkyl, C 1-6 alkoxy, hydroxyl, oxo, aryloxy, haloC 1-6 alkyl, haloC 1-6 alkoxy and carboxyl. Each of these optional substituents may be optionally substituted with any of the optional substituents described above, including nitro, amino, substituted amino, cyano, heterocyclyl (including non-aromatic heterocyclyl and heteroaryl), C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxyl, haloC 1-6 alkyl, haloC 1-6Alkoxy, halo, hydroxyl, and carboxyl compounds are preferred.

[0085] In nomenclature of mixed substituents, such as haloalkyl and alkylaryl, the order of the groups should be understood as having no directional intent, and therefore the bonding site may be to any of the parts included in the mixed group. For example, the terms "alkylaryl" and "arylalkyl" are intended to refer to the same group, and the bonding site may be via the alkyl or aryl part (or both in the case of a divalent species).

[0086] A "chelate ligand" refers to a functional group or group of functional groups suitable for bonding with a metal atom to form a polydentate coordination complex. A chelate ligand may form two, three, four, or more coordination bonds with a metal atom and therefore may contain two, three, four, or more ligand moieties. The group of functional groups in a chelate ligand may contain different functional groups within a single group (for example, a carboxylic acid and a hydroxyl functional group may be present in a single chelate ligand).

[0087] [ka] A description of the hydroxamic acid moiety like this is understood to include both positive and reverse (or retro) hydroxamic acids. Therefore, the structure [ka] R 1 but [ka] And, [ka] and [ka] It is understood to include both.

[0088] A "nuclide" refers to an isotope of a metal, which can undergo radioactive decay or other processes.

[0089] A "radioactive nuclide" refers to an isotope of a metal that undergoes radioactive decay.

[0090] As used herein, “medicinal potential” includes therapeutic, diagnostic, and / or prognostic potential. The medicinal potential radionuclides referred herein are intended for pharmaceutical use and for forming stable complexes with compounds. Any suitable oxidation state is acceptable.

[0091] As used herein, unless the context requires otherwise, the term "comprise," and its variations such as "comprising," "comprises," and "comprised," are not intended to exclude additional additives, ingredients, integers, or steps.

[0092] It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include the plural unless otherwise clearly indicated by the context. Therefore, for example, a reference to "a salt" may include multiple salts, and a reference to "at least one heteroatom" may include one or more heteroatoms.

[0093] The term "and / or" can mean "and" or "or".

[0094] The term "(s) (including plural)" following a noun can refer to the singular, plural, or both forms.

[0095] Various features of the present invention are described with reference to specific values ​​or ranges of values. These values ​​are intended to refer to the results of various appropriate measurement techniques and should therefore be interpreted as including error ranges inherent to all specific measurement techniques. Some of the values ​​referred to herein are indicated with the term “about” to at least partially explain this variability. When used to describe a value, the term “about” may represent a quantity within ±25%, ±10%, ±5%, ±1%, or ±0.1% of that value.

[0096] "Metal" refers to any metal in any oxidized state. Those skilled in the art will understand that it may refer to a metal in an oxidized state suitable for use, for example, one that is suitable for forming complexes with the compounds of the present invention and / or dissolving in the mixture.

[0097] Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent by considering the following description as an example and by referring to the accompanying drawings. [Brief explanation of the drawing]

[0098] Embodiments of the present invention will be further described with reference to the following non-limiting drawings.

[0099] Figure 1 shows the general characteristics of various forms of compounds of the present invention and specific embodiments of those general characteristics. Specifically,

[0100] [Figure 1a] Figure 1a shows a two-component compound of the present invention, in which one component is a chelate ligand selective for 89Zr and the other compound is a chelate ligand selective for a pharmaceutically acceptable nuclide other than 89Zr. Figure 1a also shows an embodiment of the two-component system in which the 89Zr-selective chelate ligand is based on DFOB and the chelate ligand selective for a pharmaceutically acceptable nuclide other than 89Zr is based on DOTA. This embodiment of the two-component system will be discussed further in Examples 1 and 2.

[0101] [Figure 1b]Figure 1b shows a three-component compound of the present invention, one of which is a chelate ligand selective for 89Zr, and the other is a chelate ligand selective for a pharmaceutically acceptable nuclide other than 89Zr. An additional component of the three-component system shown in Figure 1b is a linker. The linker may optionally contain substituents that can form a target moiety or a conjugate with the target moiety. When a linker is present, such features allow the compound to be biologically targeted. Figure 1b also shows an embodiment of the three-component system, in which a linker is present, the chelate ligand selective for 89Zr is based on DFOB, the chelate ligand selective for a pharmaceutically acceptable nuclide other than 89Zr is based on DOTA, and the linker is based on lysine. The lysine-based linker contains a free amino group, which is a substituent that can form a conjugate with the target moiety, or is further modified to attach a functional group further away from the compound's backbone for the purpose of enabling the conjugate formation of the target moiety. This embodiment of the three-component system is discussed further in Examples 3 and 4.

[0102] [Figure 1c] Figure 1c shows a three-component compound of the present invention, in which one component is a chelate ligand selective for 89Zr, and one component is a chelate ligand selective for a radionuclide other than 89Zr that has potential as a pharmaceutical. The additional component of the three-component system shown in Figure 1c is a part that enhances the 89Zr affinity of the 89Zr-selective chelate ligand.

[0103] [Figure 1d]Figure 1d shows a four-component compound of the present invention, one of which is a chelate ligand selective for 89Zr, one of which is a chelate ligand selective for other potentially pharmaceutically active radionuclides besides 89Zr, one of which is a linker, and the other components are moieties that enhance the 89Zr affinity of the 89Zr-selective chelate ligand. The linker may optionally contain substituents that can form a target moiety or a conjugate with the target moiety, or that are further modified to attach functional groups further away from the compound's backbone for the purpose of enabling the formation of a conjugate of the target moiety. When a linker is present, such features allow the compound to be biologically targeted. Figure 1d also shows an embodiment of a four-component system, in which the 89Zr-selective chelate ligand is based on DFOB, the chelate ligand selective to other potentially pharmaceutically acceptable radionuclides besides 89Zr is based on DOTA, the linker is based on lysine, and the moiety that enhances the 89Zr affinity of the 89Zr-selective chelate ligand is based on 5-((5-aminopentyl)(hydroxy)amino)-5-oxopentanoic acid (PPH). The lysine-based linker contains a free amino group, which can form a conjugate with the target moiety, or is a substituent that is further modified to attach a functional group further away from the compound's backbone for the purpose of enabling the conjugate formation of the target moiety. This three-component system embodiment is discussed further in Example 5.

[0104] [Figure 2a] Figure 2a shows the liquid chromatography-mass spectrometry spectra of the semi-purified two-component solutions of Example 1 and Example 2. Specifically, the DFOB-DOTA(2) of Example 1 is shown as the total ion current (top) or as the EIC trace (bottom) (black).

[0105] [Figure 2b]Figure 2b shows the liquid chromatography-mass spectrometry spectrum of the semi-purified two-component solution of Example 2. Specifically, DFOB-DOTA(2), formed by loading Zr(IV) from Example 2a to form Zr(IV)-2, is shown as the total ion current (top) or as the EIC trace (bottom) (black). The EIC trace (black) corresponds to Zr(IV)-DFOB-DOTA(Zr(IV)-2) as a 1:1 metal:ligand stoichiometric complex. The signal corresponding to the EIC value of Zr(IV)2-DFOB-DOTA([M]2+) (gray) is the baseline, and this signal supports the 1:1 stoichiometric amount.

[0106] [Figure 2c] Figure 2c shows the liquid chromatography-mass spectrometry spectrum of the semi-purified two-component solution of Example 2. Specifically, DFOB-DOTA(2), formed by loading Lu(III) from Example 2b to form Lu(III)-2, is shown as the total ion current (top) or as the EIC trace (bottom) (black). The EIC trace (black) corresponds to Lu(III)-DFOB-DOTA(Lu(III)-2) as a 1:1 metal:ligand stoichiometric complex. The signal corresponding to the EIC value of Lu(III)2-DFOB-DOTA([M+2H]2+) (gray) is the baseline, and this signal supports the 1:1 stoichiometric amount.

[0107] [Figure 3a] Figure 3a shows the mass spectrometry spectrum of the maximum peak of the two-component system of DFOB-DOTA(2) in Example 1, either as experimental data (top) or calculated (theoretical) data (bottom).

[0108] [Figure 3b] Figure 3b shows the mass spectrometry spectrum of the maximum peak of the two-component system in Example 2, either as experimental data (top) or calculated (theoretical) data (bottom). Specifically, DFOB-DOTA(2), obtained by loading Zr(IV) to form Zr(IV)-2 of Example 2a, is shown as experimental data (top) or calculated (theoretical) data (bottom).

[0109] [Figure 3c] Figure 3c shows the mass spectrometry spectrum of the maximum peak of the two-component system in Example 2, either as experimental data (top) or calculated (theoretical) data (bottom). Specifically, DFOB-DOTA(2), obtained by loading Lu(III) to form Lu(III)-2 of Example 2b, is shown as experimental data (top) or calculated (theoretical) data (bottom).

[0110] [Figure 4a] Figures 4a-4c show the liquid chromatography-mass spectrometry spectra of the three-component solutions of Examples 3 and 4 purified by HPLC. Specifically, DFOB-L-LYS-DOTA(3) from Example 3 (Figure 4a), DFOB-L-LYS-DOTA(3) loaded with Zr(IV) to form Zr(IV)-3 from Example 4a (Figure 4b), or DFOB-L-LYS-DOTA(3) loaded with Lu(III) to form Lu(III)-3 from Example 4b (Figure 4c) are shown as total ion current (top) or EIC trace (bottom). The EIC traces correspond to Zr(IV)-DFOB-L-LYS-DOTA(Zr(IV)-3) or Lu(III)-DFOB-L-LYS-DOTA(Lu(III)-3) as 1:1 metal:ligand stoichiometric complexes. Signals corresponding to EIC values ​​of Zr(IV)2-DFOB-L-LYS-DOTA([M]2+) or Lu(III)2-DFOB-L-LYS-DOTA([M+2H]2+) (gray in their respective panels) represent the baseline, and these signals support the 1:1 stoichiometric quantity. [Figure 4b]Figures 4a-4c show the liquid chromatography-mass spectrometry spectra of the three-component solutions of Examples 3 and 4 purified by HPLC. Specifically, DFOB-L-LYS-DOTA(3) from Example 3 (Figure 4a), DFOB-L-LYS-DOTA(3) loaded with Zr(IV) to form Zr(IV)-3 from Example 4a (Figure 4b), or DFOB-L-LYS-DOTA(3) loaded with Lu(III) to form Lu(III)-3 from Example 4b (Figure 4c) are shown as total ion current (top) or EIC trace (bottom). The EIC traces correspond to Zr(IV)-DFOB-L-LYS-DOTA(Zr(IV)-3) or Lu(III)-DFOB-L-LYS-DOTA(Lu(III)-3) as 1:1 metal:ligand stoichiometric complexes. Signals corresponding to EIC values ​​of Zr(IV)2-DFOB-L-LYS-DOTA([M]2+) or Lu(III)2-DFOB-L-LYS-DOTA([M+2H]2+) (gray in their respective panels) represent the baseline, and these signals support the 1:1 stoichiometric quantity. [Figure 4c] Figures 4a-4c show the liquid chromatography-mass spectrometry spectra of the three-component solutions of Examples 3 and 4 purified by HPLC. Specifically, DFOB-L-LYS-DOTA(3) from Example 3 (Figure 4a), DFOB-L-LYS-DOTA(3) loaded with Zr(IV) to form Zr(IV)-3 from Example 4a (Figure 4b), or DFOB-L-LYS-DOTA(3) loaded with Lu(III) to form Lu(III)-3 from Example 4b (Figure 4c) are shown as total ion current (top) or EIC trace (bottom). The EIC traces correspond to Zr(IV)-DFOB-L-LYS-DOTA(Zr(IV)-3) or Lu(III)-DFOB-L-LYS-DOTA(Lu(III)-3) as 1:1 metal:ligand stoichiometric complexes. Signals corresponding to EIC values ​​of Zr(IV)2-DFOB-L-LYS-DOTA([M]2+) or Lu(III)2-DFOB-L-LYS-DOTA([M+2H]2+) (gray in their respective panels) represent the baseline, and these signals support the 1:1 stoichiometric quantity.

[0111] [Figure 5a] Figures 5a to 5c show the mass spectrometry spectra of the maximum peak of the three-component systems of Example 3 and Example 4, specifically showing DFOB-L-LYS-DOTA(3) of Example 3 (Figure 5a), or DFOB-L-LYS-DOTA(3) of Example 4a loaded with Zr(IV) to form Zr(IV)-3 (Figure 5b), or DFOB-L-LYS-DOTA(3) of Example 4b loaded with Lu(III) to form Lu(III)-3 (Figure 5c), as experimental data (upper) or calculated (theoretical) data (lower). [Figure 5b] Figures 5a to 5c show the mass spectrometry spectra of the maximum peak of the three-component systems of Example 3 and Example 4, specifically showing DFOB-L-LYS-DOTA(3) of Example 3 (Figure 5a), or DFOB-L-LYS-DOTA(3) of Example 4a loaded with Zr(IV) to form Zr(IV)-3 (Figure 5b), or DFOB-L-LYS-DOTA(3) of Example 4b loaded with Lu(III) to form Lu(III)-3 (Figure 5c), as experimental data (upper) or calculated (theoretical) data (lower). [Figure 5c] Figures 5a to 5c show the mass spectrometry spectra of the maximum peak of the three-component systems of Example 3 and Example 4, specifically showing DFOB-L-LYS-DOTA(3) of Example 3 (Figure 5a), or DFOB-L-LYS-DOTA(3) of Example 4a loaded with Zr(IV) to form Zr(IV)-3 (Figure 5b), or DFOB-L-LYS-DOTA(3) of Example 4b loaded with Lu(III) to form Lu(III)-3 (Figure 5c), as experimental data (upper) or calculated (theoretical) data (lower).

[0112] [Figure 6] Figure 6 shows the liquid chromatography-mass spectrometry spectrum of the semi-purified four-component system solution of Example 5. Specifically, DFOB-PPH-L-LYS-DOTA(4) is presented as the total ion current (upper) or the EIC trace of the [M+3H]³⁺ (black) or [M+4H]⁴⁺ (grey) adduct (lower). This complex is expected to be labeled with metal ions similarly to the two-component system and the three-component system.

[0113] [Figure 7] Figure 7 shows the structure of the positive hydroxamic acid 5-((5-aminopentyl)(hydroxy)amino)-5-oxopentanoic acid (PPH), and the corresponding system DFOB-PPH-L-LYS-DOTA (4) is shown in Figure 7 together with the corresponding reverse hydroxamic acid 4-(6-amino-N-hydroxyhexanamido)butanoic acid (retro-PPH) and the related 4-component system DFOB-(retro-PPH-L-LYS-DOTA ((retro-4)).

[0114] [Figure 8] Figure 8 shows the liquid chromatography-mass spectrometry spectrum of the solution of the semi-purified product of Example 9 and the mass spectrometry of the maximum peak of the semi-purified product of Example 9.

[0115] [Figure 9] Figure 9 shows the liquid chromatography-mass spectrometry (TIC) spectrum of the semi-purified reaction mixture containing DFOB-L-LYS-EPS-PEG4-DOTA of Example 10.

[0116] [Figure 10] Figure 10 shows the MS isotope pattern derived from the LC signal at 7.52 minutes (Figure 9), corresponding to DFOB-L-LYS-EPS-PEG4-DOTA of Example 10.

[0117] [Figure 11] Figure 11 shows the extracted ion chromatogram (EIC, m / z=661.885) corresponding to the [M+2H]2+ adduct of DFOB-L-LYS-EPS-PEG4-DOTA of Example 10.

[0118] [Figure 12] Figure 12 shows the extracted ion chromatogram (EIC, m / z=441.59) corresponding to the [M+3H]3+ adduct of DFOB-L-LYS-EPS-PEG4-DOTA of Example 10.

[0119] [Figure 13]Figure 13 shows the liquid chromatography-mass spectrometry (TIC) spectrum of the reaction mixture containing NCS-activated DFOB-L-LYS-EPS-PEG4-DOTA (Compound D2) of Example 11.

[0120] [Figure 14] Figure 14 shows the MS isotope pattern of the LC signal (Figure 13) at 11.171 to 12.032 minutes, corresponding to NCS-activated DFOB-L-LYS-EPS-PEG4-DOTA (Compound D2) of Example 11.

[0121] [Figure 15] Figure 15 shows the selected ion monitoring (SIM, m / z=757.9) corresponding to the [M+2H]2+ adduct of NCS-activated DFOB-L-LYS-EPS-PEG4-DOTA (Compound D2) of Example 11.

[0122] [Figure 16] Figure 16 shows the selected ion monitoring (SIM, m / z=505.6) corresponding to the [M+3H]3+ adduct of NCS-activated DFOB-L-LYS-EPS-PEG4-DOTA (Compound D2) of Example 11.

[0123] [Figure 17] Figure 17 shows the relative cell-bound fraction ratio of DOTA-mAb[177Lu] at 30 minutes, 1 hour and 2 hours.

[0124] [Figure 18] Figure 18 shows the relative cell-bound fraction ratio of Compound D2-mAb[177Lu] at 30 minutes, 1 hour and 2 hours.

[0125] [Figure 19] Figure 19 shows the relative cell-bound fraction ratio of DFOB-mAb[89Zr] at 30 minutes, 1 hour and 2 hours.

[0126] [Figure 20]Figure 20 shows the relative cell binding fraction ratios of compound D2-mAb[89Zr] at 30 minutes, 1 hour, and 2 hours.

[0127] [Figure 21] Figure 21 shows coronal PET images of compound D2-mAb[89Zr] (top row) or DFOB-mAb[89Zr] (bottom row) at 4 hours, 24 hours, or 48 hours.

[0128] [Figure 22] Figure 22 shows the in vivo distribution of DFO-mAb[89Zr] and compound D2-mAb[89Zr] 48 hours after injection, as determined by ROI analysis of PET cross-sectional images.

[0129] [Figure 23] Figure 23 shows the in vitro and intracellular distribution of DFO-mAb[89Zr], DFO-mAb[177Lu], compound D2-mAb[89Zr], and compound D2-mAb[177Lu] within the tumor 48 hours after injection, as determined by in vitro gamma-ray counting. [Modes for carrying out the invention]

[0130] The present invention relates to a compound comprising two different chelate ligands, each chelate ligand selected to form a complex with a different nuclide exhibiting sufficient affinity and / or selectivity for pharmaceutically acceptable use.

[0131] The inventors developed a compound containing two different chelate ligands, and upon immediate exposure to a suitable radionuclide with medicinal potential, it formed a single stable complex. Surprisingly, this complex does not arise as a mixture of coordination isomers with different metallic bonding modes, despite the compound having multiple possible binding sites. Furthermore, exposure to different suitable radionuclides with medicinal potential leads to the formation of different single stable complexes with different chelate ligands. Remarkably, these different complexes do not result in multiple possible binding sites in the compound. Despite the presence of multiple possible binding sites, the compound does not arise as a mixture of multiple bonding modes. Furthermore, this compound can form complexes with two different metals, each bound by a different chelate ligand. Surprisingly, this complex also does not arise as a mixture of multiple bonding modes, despite the compound having a mixture of multiple possible binding sites.

[0132] Prior to the present invention, a potential problem with compounds or compositions comprising different chelate ligands for complexing with a given nuclide was thought to be that performance might be impaired as a result of the presence of different chelate ligands. It was also thought that a given radionuclide might bind to both chelate ligands to varying degrees, which could make it difficult to ensure robust radiolabeling. For example, it was thought that such interactions could interfere with the normal affinity of the chelate ligands to the given nuclide, especially when different chelate ligands are present in the same compound, such as when the local concentration of the other chelate ligand is higher. Advantageously, in at least preferred embodiments of the present invention, each chelate ligand can bind to the target nuclide with sufficient affinity and selectivity, despite the presence of other possible chelators in the same compound.

[0133] In some situations, it is advantageous to administer one or more pharmaceutically active metals, including one or more pharmaceutically active radionuclides, to a target simultaneously or nearly simultaneously. However, prior to the present invention, it was thought that simultaneous administration of one or more pharmaceutically active radionuclides would complicate administration due to problems arising from the differing pharmacokinetics of multiple suitable ligands. Advantageously, the compounds of the present invention can complex with one or more pharmaceutically active metals, including pharmaceutically active radionuclides. This strategy simplifies the pharmacokinetics when one or more pharmaceutically active metals are administered simultaneously or nearly simultaneously. However, the ligands of pharmaceutically active radionuclides, suitable for pharmacokinetic use, need to be optimized for both pharmacokinetics and complex formation with respect to the pharmaceutically active radionuclides. Any structural changes to such optimized ligand structures can interfere with the pharmacokinetics and / or affinity of the ligand complex, potentially making the complex less suitable as a pharmaceutical. Surprisingly, despite structural changes in the ligands and compounds, the complexes of the compounds of the present invention with pharmaceutically active metals remain suitable as pharmaceuticals. This holds true even when different ligands are present in the compound, and includes cases where the compound forms complexes with one or more metals that have medicinal potential (e.g., metals containing radionuclides that have diagnostic potential, and metals containing radionuclides that have therapeutic potential).

[0134] In one embodiment of the present invention, 89 A first chelate ligand selective for Zr, and 89 It contains a second chelate ligand that is selective for radionuclides other than Zr that have potential as pharmaceuticals, These first and second chelate ligands are covalently bonded by a linker group. A compound is provided.

[0135] These first and second chelate ligands may be bound by any suitable means. In some embodiments, the linker is a covalent linker.

[0136] In some embodiments, the compounds of the present invention are of formula (I) [ka] A compound of, A is 89 It is a first chelate ligand that is selective for Zr, B is 89 It is a second chelate ligand that is selective for radionuclides other than Zr that have potential as pharmaceuticals, and L is a linker group. It is a compound.

[0137] In some embodiments, two different chelate ligands differ in their affinity and / or selectivity for pharmaceutically promising nuclides such that, after a suitable equilibrium time, the nuclide substantially forms a stable complex with a single chelate ligand of the compound.

[0138] In this context, "substantially" means that at least 90% of the nuclides that form compounds and complexes are 89 At least 90% of the nuclides that bind to Zr via selective chelate ligands or form complexes with compounds are 89 This indicates selective binding to radionuclides other than Zr that have potential as pharmaceuticals, via a chelate ligand.

[0139] "Equilibrium time" refers to the time elapsed since the introduction of a nuclide into a compound. Typically, both the nuclide and the compound are dissolved in the solution before the nuclide is introduced into the compound. Those skilled in the art will understand that equilibrium can be influenced by factors such as concentration, temperature, pH, the presence of competing ions, and the presence of additional solvents.

[0140] A "stable complex" means that the complex between the nuclide and the chelate ligand is not harmed by dissociation that would make it unsuitable for pharmaceutical use. The stability of a complex is determined by K d It may be quantified using dissociation constants such as the following.

[0141] In some embodiments, after a suitable equilibrium time, at least 95% of the nuclides that form complexes with the compound 89 At least 95% of the nuclides that bind to Zr via selective chelate ligands or form complexes with compounds are 89 It binds to pharmacopoeias other than Zr via a selective chelate ligand. In some embodiments, after a suitable equilibrium time, at least 99% of the nuclides that form a complex with the compound are 89 At least 99% of the nuclides that bind to Zr via selective chelate ligands or form complexes with compounds are 89 It binds to pharmacopoeias other than Zr via a selective chelate ligand. In some embodiments, after a suitable equilibrium time, at least 99.9% of the nuclides that form a complex with the compound are 89 At least 99.9% of the nuclides that bind to Zr via selective chelate ligands or form complexes with compounds are 89 It binds to radionuclides other than Zr that have potential as pharmaceuticals via selective chelate ligands.

[0142] In some embodiments where the nuclide is a radioactive nuclide, suitable equilibrium times are when one of the chelate ligands has a selective radioactive nuclide with a half-life of less than 10, less than 5, less than 2.5, less than 1, less than 0.75, less than 0.5, less than 0.25, less than 0.1, less than 0.05, or less than 0.01.

[0143] In some embodiments, suitable equilibrium times are 1 second, 5 seconds, 10 seconds, 30 seconds, and 1 minute. The appropriate equilibrium time is 2 minutes, 5 minutes, 10 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 16 hours, or 1 day. Preferably, the appropriate equilibrium time is less than 2 hours. Preferably, the appropriate equilibrium time is less than 3 hours.

[0144] In some embodiments, the stability of the nuclide chelate ligand complex is such that the stability constant (logβ) of the complex is 10 or greater, 15 or greater, 20 or greater, 25 or greater, 25.4 or greater, 30 or greater, 35 or greater, 40 or greater, 41 or greater, 45 or greater, 50 or greater, or 60 or greater.

[0145] In some embodiments, the affinity between nuclides in which the chelate ligand is selective, and the affinity between a nuclide and a radionuclide and a non-selective chelate ligand, differs by a value of at least 10, 15, 20, 25, 25.4, 30, 35, 40, 41, 45, 50, or 60 in the stability constant (logβ) of the complex between the nuclide and the two different chelate ligands. The selectivity is preferably different by a value of 25, 25.4, 40, or 41.

[0146] In some embodiments, selectivity and / or affinity are evaluated in a mixture in which all components can be dissolved. In some embodiments, selectivity and / or affinity are evaluated in a composition suitable for administration. In some embodiments, selectivity and / or affinity are evaluated post-administration in a mixture withdrawn from the subject. In some embodiments, selectivity and / or affinity are evaluated in a composition designed to mimic the post-administration mixture withdrawn from the subject.

[0147] In some embodiments, the first chelate ligand has substantially no affinity for the second chelate ligand to bind to a selective metal.

[0148] First chelate ligand The first chelate ligand is 89 It is selective for Zr. In some embodiments, the first chelate ligand is 89 It is selective for Zr(IV).

[0149] In some embodiments, the first chelate ligand is also 90 It is also selective for other radionuclides with potential as pharmaceuticals, such as Nb.

[0150] In some embodiments, the first chelate ligand is also 89 It is also selective for one or more other radionuclides with potential as pharmaceuticals, in addition to Zr.

[0151] In some embodiments, the first chelate ligand comprises one or more hydroxamic acid or hydroxypyridone groups. The hydroxamic acid or hydroxypyridone functional groups are 89 It is a suitable ligand for Zr.

[0152] In some embodiments, the first chelate ligand is hexadentate. In some embodiments, the first chelate ligand is octadentate.

[0153] In some embodiments, the first chelate ligand is a group of desferrioxamine B (DFOB).

[0154] In some embodiments, this compound further, 89 A chelate ligand selective for Zr 89 It contains a moiety that enhances Zr affinity. Preferably, the compound contains 89 A chelate ligand selective for Zr 89 The presence of a region that enhances Zr affinity allows for the formation of complexes with the compound. 89 Almost all Zr is eight-coordinate, meaning the eight atoms of the chelate ligand are connected to the atom. This indicates that it cooperates in the formation of the complex (coordination number is 8). Preferably, it forms a complex with the compound. 89 Almost all of Zr is eight-coordinate via a donor oxygen atom present in the hydroxamic acid functional group.

[0155] In some embodiments, 89The part that enhances Zr affinity is 5-((5-aminopentyl)(hydroxy)amino)-5-oxopentanoic acid (PPH), 5-((2-(2-aminoethoxy)ethyl)(hydroxy)amino)-5-oxopentanoic acid (PPH- N O), 2-(2-((5-aminopentyl)(hydroxy)amino)-2-oxoethoxy)acetic acid (PPH- C O), 2-(2-((2-(2-aminoethoxy)ethyl)(hydroxy)amino)-2-oxoethoxy)acetic acid (PPH- N O C O), 2-((2-((5-aminopentyl)(hydroxy)amino)-2-oxoethyl)thio)acetic acid (PPH- C S) and 2-((2-((2-(2-aminoethoxy)ethyl)(hydroxy)amino)-2-oxoethyl)thio)acetic acid (PPH- N O C You may choose from S).

[0156] In some embodiments of the compound of formula (I), A is [ka] And, R 1 teeth, [ka] And, Y is CH2, O, or S. X is CH2, O, or S. Each Z is independently selected from CH2 or O. N is either 0 or 1, and M is either 0 or 1.

[0157] In some embodiments, Z in all examples is CH2.

[0158] In some embodiments, Z is O in all examples. Methods for synthesizing compounds in which Z is O are known in the art, for example, in International Publication No. 2017 / 096430.

[0159] In some embodiments, Y is CH2 or O.

[0160] In some embodiments, X is CH2 or O.

[0161] In some embodiments, n is 0.

[0162] In some embodiments, n is 1,

[0163] Y is CH2, O, or S.

[0164] X is CH2, O, or S, and

[0165] m is either 0 or 1.

[0166] In some embodiments, n is 1,

[0167] Y is either CH2 or O.

[0168] X is either CH2 or O, and

[0169] M is either 0 or 1.

[0170] In some embodiments, n is 1, Y is CH2, X is CH2, and m is 1.

[0171] In some embodiments, n is 1, Y is CH2, X is CH2, and m is 0.

[0172] In some embodiments, n is 1, Y is CH2, X is O, and m is 0.

[0173] In some embodiments, n is 1, Y is CH2, X is O, and m is 1.

[0174] In some embodiments, n is 1, Y is O, X is CH2, and m is 1.

[0175] In some embodiments, n is 1, Y is 0, X is 0, and m is 1.

[0176] In some embodiments, n is 1, Y is S, X is CH2, and m is 1.

[0177] In some embodiments, n is 1, Y is S, X is O, and m is 1.

[0178] In some embodiments, A is [ka] and [ka] It is selected from the group consisting of the following.

[0179] Second chelate ligand The second chelate ligand is, 89 It is selective for radionuclides other than Zr that have potential as pharmaceuticals.

[0180] In some embodiments, the second chelate ligand is 90 Y, 153 Sm, 161 Tb, 177 Lu, 213 Bi and 225 It is selective to one or more nuclides from the group consisting of Ac. In some embodiments, 90 Y is 90Y(III) may be Y(III). In some embodiments, 153 Sm, 153 It may be Sm(III). In some embodiments, 161 Tb is 161 It may be Tb(III). In some embodiments, 213 Bi is 213 It may be Bi(III). Several implementations In terms of form, 225 Ac is 225 The second chelate ligand may be Ac(III). The reference is [Mishiro, K.; Hanaoka, H.; Yamaguchi, A.; Ogawa, K. Radiotheranostics with It may be selective for various trivalent metals, such as those known in [radiolanthanides: Design, development strategies, and medical applications. Coord. Chem. Rev. 2019, 383, 104-131].

[0181] In some embodiments, the second chelate ligand comprises a polyaminocarboxylic acid group. The polyaminocarboxylic acid group is 90 Y(III), 153 Sm, 161 Tb, 177 Lu(III), 213 Bi(III) and 225 It is a suitable chelate ligand for Ac(III). Furthermore, the polyaminocarboxylic acid group also requires high temperatures (99°C) and long reaction times (2 hours) to form these complexes, resulting in only a moderate radiochemical yield (65%). 89 It is also a relatively inferior chelator of Zr. These high temperatures and long reaction times are not very compatible with molecules containing many functional groups and sensitive biomolecules such as antibodies that can be present in compounds for immunological applications.

[0182] In some embodiments, the second chelate ligand is a group of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), DOTAGA (α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), or NETA (7-[2-[bis(carboxymethyl)amino]ethyl]hexahydro-1H-1,4,7-triazonine-1,4(5H)-diacetic acid).

[0183] In some embodiments of the compound of formula (I), B is [ka] and [ka] It is selected from the group consisting of the following.

[0184] In some embodiments of the compound of formula (I), B is [ka] That is the case.

[0185] Linker group The first and second chelate ligands are bound via a linker group.

[0186] The linker group may define any suitable bond between the two chelate ligands.

[0187] In some embodiments, the linker group is covalent.

[0188] In some embodiments, the linker group may be any suitable divalent species that functions to form a covalent bond with a first chelate ligand and a covalent bond with a second chelate ligand.

[0189] In any linker group, the pathway from the first chelate group to the second chelate group may be defined by the shortest path passing through the minimum number of atoms. The linker group may therefore be defined by the shortest linear covalent bond between the two chelate ligands. For example, in the structure shown in Figure 1a, the linker group is a covalent bond with zero atoms between the first and second chelate ligands, whereas in the structure shown in Figure 1b, the linker group has seven atoms in the shortest path (including the amide carbonyl covalently bonded to the N atom of the DFOB moiety and the amide nitrogen atom covalently bonded to the DOTA moiety).

[0190] The shortest chain of linker groups may have up to 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0 atoms. In some embodiments, the shortest chain may be between any of these values ​​and any other, such as 1 to 30 atoms or 4 to 10 atoms.

[0191] The linker may be a linear atom covalently bonded to the first chelate ligand and the second chelate ligand, and may include any degree of branching or substitution. In some embodiments, the linker group may include one or more cyclic structures, which may be selected from optionally substituted cycloalkyl, optionally substituted aryl, or optionally substituted heterocyclyl groups, and these structures may optionally be condensed, crosslinked, or included in a spirocycle system.

[0192] Suitable linker atoms include carbon (C), nitrogen (N), oxygen (O), and sulfur (S). The linker atom bonds to other atoms, such as hydrogen (H), in a manner that satisfies the usual laws of valence. The linker group can be saturated or unsaturated.

[0193] In some embodiments, the linker group is optionally substituted C, interrupted by one or more functional groups selected from heteroatoms, alkenes, alkynes, cycloalkyl groups, heterocyclyl groups, amides, esters, ketones, and target moieties.1~20 It is an alkyl chain. In some embodiments, the alkyl chain of the linker is interrupted by 10 or fewer groups, 8 or fewer groups, 6 or fewer groups, 4 or fewer groups, 3 or fewer groups, 2 or fewer groups, or 1 group.

[0194] In some embodiments, the linker group is an oligopeptide containing 10 or fewer amino acid residues, 8 or fewer amino acid residues, 6 or fewer amino acid residues, 4 or fewer amino acid residues, 3 or fewer amino acid residues, or 2 or fewer amino acid residues. In some embodiments, the linker group contains one amino acid residue. In some embodiments, the amino acid residues are selected from 20 naturally occurring amino acids, usually indicated by a three-letter symbol, and also include 4-hydroxyproline, hydroxylysine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, and ornithine. In some embodiments, the amino acid residues are selected from 20 naturally occurring amino acids, usually indicated by a three-letter symbol. Preferably, the linker group contains lysine, glutamic acid, aspartic acid, or a combination thereof. Preferably, the linker contains lysine. Preferably, the linker contains glutamic acid. Preferably, the linker contains aspartic acid.

[0195] In some embodiments, the linker is a conjugate of L-glutamic acid. In some embodiments, the linker is a conjugate of D-glutamic acid. In some embodiments, the linker is a conjugate that binds to one of the chelate ligands via the α-carboxylic acid of glutamic acid. In some embodiments, the linker is a conjugate that binds to one of the chelate ligands via the γ-carboxylic acid of glutamic acid.

[0196] In some embodiments, the linker is a conjugate of L-aspartic acid. In some embodiments, the linker is a conjugate of D-aspartic acid. In some embodiments, the linker is a conjugate that binds to one of the chelate ligands via the α-carboxylic acid of aspartic acid. In some embodiments, the linker is a conjugate that binds to one of the chelate ligands via the β-carboxylic acid of aspartic acid.

[0197] In some embodiments, the linker is an L-lysine conjugate. In some embodiments, the linker is a D-lysine conjugate. In some embodiments The linker is a conjugate that binds to one of the chelate ligands via the α-amine of lysine. In some embodiments, the linker is a conjugate that binds to one of the chelate ligands via the ε-amine of lysine. In some embodiments, the linker group comprises one or more ethylene glycol repeating units.

[0198] The linker is optionally substituted with one or more substituents. Optional substituents include C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~8 Cycloalkyl, hydroxyl, oxo, C 1~6 Alkoxy, aryloxy, C 1~6 Alkoxyaryl, Halo, C 1~6 Alkyl halos (CF3, etc.), C 1~6 Alkoxyhalo (OCF3, etc.), carboxyl, ester, cyano, nitro, amino, substituted amino, disubstituted amino, acyl, ketone, substituted ketone, amide, aminoacyl, substituted amide, disubstituted amide, thiol, C 1-6 Alkylthio, thioxo, sulfuric acid, sulfonic acid, sulfinyl, substituted sulfinyl, sulfonyl, substituted sulfonyl, sulfonylamide, substituted sulfonamide, disubstituted sulfonamide, aryl, aryl C 1~6Examples include alkyl, heterocyclyl, and heteroaryl groups, and each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl group, as well as groups containing these, may be further optionally substituted. The optionally substituted groups may be further substituted with one, two, three, four, or more groups selected from the groups defined above, preferably one, two, or three, or more, more preferably one or two groups.

[0199] In another embodiment, the present invention relates to formula (II) [ka] A compound of, Ch 1 It contains the DFOB base, Ch 2 It includes the basis of DOTA, and L is a linker group. Provides compounds.

[0200] Ch 1 This may be any group of DFOB suitable for forming a covalent bond with the linker group. 1 Ch may be any group of the DFOB described herein for the first chelate ligand. In some embodiments, Ch 1 DFOB 89 Includes a portion that enhances affinity for Zr. In some embodiments, Ch 1 The following substructure [ka] It has, R 1 teeth, [ka] And, Y is CH2, O, or S. X is CH2, O, or S. N is either 0 or 1, and M is either 0 or 1.

[0201] In some embodiments, m is 0 and Y is CH2. In some embodiments, m is 1 and Y is CH2, O, or S.

[0202] Ch 2 It may have any group structure of DOTA that is suitable for forming a covalent bond with the linker group. 1 may be any group of the DOTA described herein for the second chelate ligand. For example, Ch 2 is a substructure, [ka] It may have.

[0203] Ch 2 It may have any group structure of DOTAGA that is suitable for forming a covalent bond with the linker group. 1 may be any group of DOTAGA described herein for the second chelate ligand. For example, Ch 2 is a substructure [ka] It may have.

[0204] Ch 2 It may have any group structure of NETA that is suitable for forming a covalent bond with the linker group. 1 may be any group of the NETA described herein for the second chelate ligand. For example, Ch 2 is a substructure [ka] It may have.

[0205] The linker group of the compound of formula (II) may be the same as any covalent linker group described herein.

[0206] target area In some embodiments, the compounds of the present invention include a target moiety or a group capable of forming a conjugate with the target moiety. Typically, the target moiety or the group capable of forming a conjugate with the target moiety may be incorporated into the linker group. In some embodiments, the linker group includes a spacer moiety extending from the linker to the target moiety or the group capable of forming a conjugate with the target moiety. The spacer may typically extend from the linker by 1 to 20 atoms (the longest linear chain) selected from C, O, and N. In some embodiments, the spacer moiety is optionally interrupted by optionally substituted C, which is optionally interrupted by 1 to 10 functional groups selected from the group consisting of ethers, hydroxyl groups, amines, and carboxylic acids, and combinations thereof. 1~20 It is an alkyl group. Advantageously, the spacer portion may contain one or more of these hydrophilic portions that help increase the solubility of the compound in an aqueous environment. In some embodiments, the spacer portion contains one or more ethers to form a polyethylene glycol portion inside the spacer. Polyethylene glycol may define part of the spacer portion, or the spacer portion may consist of polyethylene glycol groups ending with a target portion or a functional group capable of forming a conjugate with the target portion. The polyethylene glycol group may contain 2 to 20 -(CH2)2O- repeating units, preferably 2 to 10 units. However, in some embodiments, the first and / or second chelate ligand may have functional groups containing a target portion or a group capable of forming a conjugate with the target portion. The group capable of forming a conjugate with the target portion may instead form a conjugate with a solid support.

[0207] The target moiety directs the compound to a target tissue, organ, receptor, or other biologically expressed composition. In some embodiments, the target moiety is selective or specific to the target organ or tissue. Suitable target moieties that may be included in the compounds of the present invention and groups that can form conjugates with the target moiety are described in International Publication No. 2017161356 (Waddas) and International Publication No. 2015140212 (Gasser). ru.

[0208] In some embodiments, the target region is suitable for immunoPET imaging. In some embodiments, the target region is suitable for the treatment of neoplastic diseases.

[0209] Generally, the target moiety may be antibodies, amino acids, nucleosides, nucleotides, aptamers, proteins, antigens, peptides, nucleic acids, enzymes, lipids, albumin, cells, sugars, vitamins, hormones, nanoparticles, inorganic carriers, polymers, single molecules, or drugs. Specific examples of target moieties include steroid hormones for the treatment of breast and prostate lesions, somatostatin, bombesin, CCK, and neurotensin receptor-binding molecules for the treatment of neuroendocrine tumors, CCK receptor-binding molecules for the treatment of lung cancer, ST receptor and carcinoembryonic antigen (CEA)-binding molecules for the treatment of colorectal cancer, dihydroxyindolecarboxylic acid and other melanin-producing biosynthetic intermediates for the treatment of melanoma, integrin receptors, fibroblast-activating protein α (FAP), and atherosclerotic plaque-binding molecules for the treatment of vascular diseases, and amyloid plaque-binding molecules for the treatment of brain lesions. Examples of target moieties also include synthetic polymers such as polyamino acids, polyols, polyamines, polyacids, oligonucleotides, aborols, dendrimers, and aptamers.

[0210] In some embodiments, the present invention relates to nanoparticles, antibodies (e.g., technetium (99mTc), fanoresomab (NeutroSpect®), girentuximab (Rencarex®), ibritumomab tiuxetan (Zevalin®), and adalimumab (Herceptin®), proteins (e.g., TCII, HSA, annexin, and Hb), peptides (e.g., octreotide, bombesin, neurotensin, and angiotensin), nitrogen-containing simple or complex carbohydrates (e.g., glucosamine and glucose), nitrogen-containing vitamins (e.g., vitamins A, B1, B2 12 The present invention relates to the incorporation of a target moiety that may be selected from among C, D2, D3, E, H, and K, nitrogen-containing hormones (e.g., estradiol, progesterone, and testosterone), nitrogen-containing active ingredients (e.g., celecoxib or other nitrogen-containing NSAIDs, AMD3100, CXCR4, and CCR5 antagonists), and nitrogen-containing steroids. In some embodiments, the present invention relates to the incorporation of the target moiety girentuximab.

[0211] In some embodiments, the compound of the present invention may be substituted with a substituent that can form a target moiety or a conjugate with the target moiety.

[0212] In some embodiments, the present invention may include conjugates of compounds, complexes, pharmaceuticals, or compositions of the present invention having multiple target moieties. For example, multiple bioactive or chemically active substances may be utilized to enhance specificity to a particular target tissue, organ, receptor, or other biologically expressed composition. In such examples, the target moieties may be identical or different. For example, a single conjugate may have multiple antibodies or antibody fragments, these antibodies or antibody fragments directed to a desired antigen or hapten. Typically, the antibodies used in a conjugate are monoclonal antibodies or antibody fragments directed to a desired antibody or hapten. Thus, for example, a conjugate may contain two or more monoclonal antibodies having specificity to a desired epitope, thereby increasing the concentration of the conjugate at the desired site. Similarly, and independently, a conjugate may contain two or more different bioactive or chemically active substances, each directed to a different site in the same target tissue or organ. By utilizing multiple target moieties in this way, the conjugate can be favorably concentrated in multiple regions of the target tissue or organ, possibly enhancing the effectiveness of a therapeutic or diagnostic treatment. In one embodiment, the target moiety may include a peptide, a protein, or dimers, trimers, and polymers of a peptide or protein. Furthermore, the conjugate is designed to concentrate the conjugate in the target tissue or organ, most advantageously achieving the desired therapeutic and / or diagnostic outcome while minimizing non-target deposition. The ratio of physiologically active or chemically active substances may be such that the mixture has a specific ratio. Alternatively, and / or moreover, the present invention relates to a two-step pretargeting method.

[0213] It is assumed that the compounds, complexes, pharmaceuticals, and compositions of the present invention can be modified to target specific receptors or cancer cells, or to persist in various in vivo environments, and therefore falls within the scope of the present invention. In modified forms, the conjugates, compositions, and methods of the present invention can be used against solid tumors, cell lines, and cell line tissues that exhibit increased nucleotide excision repair and increased other resistance mechanisms.

[0214] In some embodiments, the compounds, complexes, pharmaceuticals, or compositions of the present invention form conjugates with one or more receptor-specific molecules, including antibodies, oligopeptides, polypeptides, or one or more small molecule compounds, that target cancer-specific receptors and / or receptors overexpressed in specific cancer types.

[0215] In some embodiments, the target portion or substituents that can form a conjugate with the target portion are selected from one or more components of groups a), b), c), d), and e), a) The group consists of OH, NH2, SH, COOH, CHO, N3, SCN, CH2X (X=Cl, Br, I), activated esters (such as N-hydroxysuccinimide, tetra or pentafluorophenol derivatives), en-one systems (such as α-β unsaturated carbonyl or Michael acceptor systems like maleimide), dienes or dienophiles, alkenes, and alkynes suitable for the Diels-Alder reaction. b) The group consists of naturally occurring polypeptides, particularly proteins, and a first click moiety that can selectively form a covalent bond with the second click moiety under reaction conditions in which the first or second click moiety does not undergo a covalent bond reaction. c) Group includes antibodies, oligopeptides, polypeptides, polynucleotides, liposomes, polymerosomes, phospholipids, vitamins, monosaccharides, oligosaccharides, nanoparticles, or target sites in cells and / or tissues. -6 Less than mol / L (<), 10 -7 mol / L, <10 -8 mol / L or <10 -9 It consists of a part that specifically binds with a mol / L binding constant, d) The group consists of antibodies, oligopeptides, polypeptides or proteins, polynucleotides, liposomes, polymerosomes, phospholipids, vitamins, monosaccharides, oligosaccharides, nanoparticles, or drug-like molecules with a molecular weight of less than 3000 U (<), all of which are selective for disease-specific ligands, cell-specific ligands, or tissue-specific ligands, and Group e) consists of solid supports.

[0216] In some embodiments, the target moiety or substituents that can form a conjugate with the target moiety are selected from the group consisting of OH, NH2, SH, COOH, N3, SCN, activated esters, maleimides, and alkynes. Preferably, OH, NH2, SH, N3, maleimides, and alkynes. More preferably, OH, NH2, N3, and alkynes. More preferably, OH and NH2. Most preferably, NH2.

[0217] In some embodiments, the target moiety or substituents capable of forming a conjugate with the target moiety include one of two partners forming a so-called click reaction pair. In such embodiments, the target moiety or substituents capable of forming a conjugate with the target moiety is a first click moiety capable of selectively forming a covalent bond with a second click moiety under reaction conditions in which the first or second moiety does not undergo a covalent reaction with naturally occurring polypeptides, particularly proteins. The click reaction group represents the formation of a conjugate between a chelate ligand and a molecule of interest, while simultaneously offering the possibility of a novel pretargeting method. In some embodiments, the target moiety or substituents capable of forming a conjugate with the target moiety include azides, alkynes, tetrazines, cyclooctines, and trans - Selected from the group consisting of cyclooctene. Suitable click reaction partners are well known in the art.

[0218] The compounds of the present invention may be provided in the form of pharmaceutically acceptable salts, solvates, tautomers, stereoisomers, polymorphs and / or prodrugs.

[0219] The term "pharmaceutically acceptable" may be used to describe any salt, solvate, tautomer, stereoisomer, polymorph and / or prodrug of the compound, or any other compound that, upon administration to a subject, can (directly or indirectly) provide the compound of the present invention or its active metabolite or residue, and is typically not unacceptable or harmful to the subject.

[0220] While salts of the compounds of the present invention are preferably pharmaceutically acceptable, salts that are not pharmaceutically acceptable are also understood to be included within the scope of this disclosure, as they may be useful, for example, as intermediates in the preparation of pharmaceutically acceptable salts or in methods that do not require administration to a subject.

[0221] Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid, boric acid, sulfamic acid, and hydrobromic acid, or salts of pharmaceutically acceptable organic acids such as acetic acid, propionic acid, butyric acid, tartaric acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, citric acid, lactic acid, mucinic acid, gluconic acid, benzoic acid, succinic acid, oxalic acid, phenylacetic acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, salicylic acid, sulfanilic acid, aspartic acid, glutamic acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, pantothenic acid, tannic acid, ascorbic acid, and valeric acid.

[0222] Examples of salts of bases include, but are not limited to, those formed with pharmaceutically acceptable cations such as sodium, potassium, lithium, calcium, magnesium, and zinc; alkylammonium salts such as those formed from ammonium and triethylamine; alkoxyammonium salts such as those formed with ethanolamine; and salts formed from ethylenediamine, choline, or amino acids such as arginine, lysine, or histidine. General information regarding the types of pharmaceutically acceptable salts and salt formations is known to those skilled in the art and is described in common texts such as "Handbook of Pharmaceutical Salts" PHStahl, CGWermuth, 1st edition, 2002, Wiley-VCH.

[0223] In the case of solid compounds, those skilled in the art will understand that the compounds, agents, and salts of the present invention may exist in various crystalline or polymorphic forms, all of which are intended to fall within the scope of the present invention and specific formulas.

[0224] The present invention encompasses all crystalline forms of the compounds of the present invention, including anhydrous crystalline forms, hydrates, solvates, and mixtures of solvates. If any of these crystalline forms exhibit polymorphism, all polymorphs are within the scope of the present invention.

[0225] The compounds of the present invention are intended to encompass, where applicable, both solvated and non-solvated forms of the compounds. Accordingly, the compounds of the present invention include compounds having the indicated structure, including hydrated or solvated forms, as well as non-hydrated and non-solvated forms.

[0226] The compounds of the present invention or their salts, tautomers, polymorphs, or prodrugs may be provided in the form of solvates. The solvates contain a stoichiometric or non-stoichiometric amount of solvent, including water, methanol, ethanol, or isopropyl alcohol, DMSO, acetonitrile, dimethylformamide (DMF), acetic acid, and similar non-covalent or bonded elements. They may be formed during the crystallization process using a pharmaceutically acceptable solvent that forms part of the crystal lattice either by occupying vacancies in the crystal lattice. Hydrates are formed when the solvent is water, and alkoxides are formed when the solvent is an alcohol. Solvates of the compounds of the present invention can be conveniently prepared or formed during the processes described herein. In general, the solvated form is considered equivalent to the non-solvated form for the purposes of the present invention.

[0227] Basic nitrogen-containing groups are replaced with C such as methyl, ethyl, propyl and butyl chlorides, bromide and iodide. 1~6 Quaternization may be performed using chemicals such as alkyl halides, dialkyl sulfates including dimethyl and diethyl sulfate, and others.

[0228] The compounds of the present invention that form crystalline solids, or their salts, tautomers, solvates, and / or prodrugs, may exhibit polymorphism. All polymorphic forms of the compounds, salts, tautomers, solvates, and / or prodrugs are within the scope of the present invention.

[0229] The compounds of the present invention may exhibit tautomerism. A tautomer is typically two interchangeable forms of a molecule that exist in equilibrium. Any tautomerism of the compounds of the present invention should be understood to be within the scope of the present invention.

[0230] A “prodrug” is a compound that does not necessarily fully meet the structural requirements of the compounds provided herein, but is modified in vivo to produce the compounds of the present invention provided herein after administration to a subject or patient. For example, a prodrug may be an acylated derivative of the compounds provided herein. Prodrugs include compounds in which a hydroxy, carboxy, amine, or sulfhydryl group is bonded to any group that, upon administration to a mammalian subject, cleaves to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate, and benzoate derivatives of alcohol and amine functional groups in the compounds provided herein. Prodrugs of the compounds provided herein may be prepared by modifying the functional groups present in the compound such that the modification cleaves in vivo to produce the parent compound.

[0231] The prodrugs include compounds in which a polypeptide chain of one amino acid residue or two or more (e.g., two, three, or four) amino acid residues is covalently bonded to the free amino and amide groups of the compound of the present invention. These amino acid residues include 20 naturally occurring amino acids, usually represented by three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, 3-methylhistidine, norvaline, β-alanine, γ-aminobutyric acid, citrulline, homocysteine, homoserine, and ornithine and methionine sulfone.

[0232] The compounds of the present invention may contain one or more stereocenters. All stereoisomers of the compounds of the present invention are within the scope of the present invention. Examples of stereoisomers include enantiomers, diastereomers, geometric isomers (E and Z olefin forms and cis and trans substitution patterns), and atropisomers. In some embodiments, the compound is a form of the compound of the present invention with many stereoisomers at any stereocenter. The compound may have at least about 60, 70, 80, 90, 95, 98, or 99% more stereoisomers of one compound than of the other.

[0233] The compounds of the present invention may be isotopically enriched with one or more isotopes of atoms present in the compound. For example, the compounds may contain the following trace amounts of isotopes: 2 H, 3 H, 13 C, 14 C, 15 N and / or 17 One or more oxygen atoms may be enriched. If the abundance of an isotope is greater than its natural abundance, it can be considered that the isotope is enriched.

[0234] complex In a further embodiment, complexes comprising the compound and metal of the present invention are provided.

[0235] In some embodiments, the metal(s) are radionuclides(s) with potential medicinal properties. In some embodiments, the metal(s) are naturally occurring, non-toxic isotopes of the metal.

[0236] In some embodiments, the complex comprises one metal. In some embodiments, the complex comprises two different metals, preferably one metal having pharmaceutical potential and the second metal having diagnostic potential.

[0237] In one or more aspects and embodiments of the present invention, the present invention also relates to compounds of the present invention that are complexes with one metal or two different metals. In some embodiments, one metal coordinates with the binding site of a first chelate ligand in the compound. In some embodiments, one metal coordinates with the binding site of a second chelate ligand in the compound. In some embodiments, one metal different from the metal bound to the first chelate ligand coordinates with the binding site of the second chelate ligand. In some embodiments, the complex contains two different metals. In some embodiments, one or both of the multiple metals are ions. In some embodiments, one or both of the two different metals are octa-coordinate, for example, the eight atoms of the first chelate ligand cooperate in complex formation with the metal (coordination number is 8), and specifically the metal is Zr or more specifically the metal is 89 It is Zr.

[0238] In some embodiments, the metal ion of the first chelate ligand is hexa-coordinate, meaning that the six atoms of the first chelate ligand cooperate in complex formation with the metal ion, specifically the metal being Zr, and more specifically the metal being 89 It is Zr. In some embodiments, the metal atom of the first chelate ligand is four-coordinate. In some embodiments, the metal atom of the first chelate ligand is five-coordinate.

[0239] In some embodiments, the metal ion of the second chelate ligand is octa-coordinate, meaning that eight atoms of the second chelate ligand are metal ions, particularly 89 It cooperates in complex formation with radionuclides other than Zr that have potential as pharmaceuticals (coordination number 8). In some embodiments, the metal ion of the second chelate ligand is heptacoordinate, meaning that the seven atoms of the second chelate ligand are metal ions, in particular 89It cooperates in complex formation with radionuclides other than Zr that have potential as pharmaceuticals (coordination number 7). In some embodiments, the metal ion of the second chelate ligand is hexa-coordinate. In some embodiments, the metal ion of the second chelate ligand is quina-coordinate. In some embodiments, the metal ion of the second chelate ligand is tetra-coordinate.

[0240] Even when the metal does not require all the coordination sites provided by the chelate ligand system, the chelate ligand enhances the stability of the complex by simply providing a high "concentration" of coordination groups near the metal, thereby protecting the complex from chelate exchange.

[0241] In some embodiments, the metal(s) of the complex have an oxidation state of +1, +2, +3, +4, +5, +6, or +7. In some embodiments, the metal(s) of the complex have an oxidation state of +3, +4, +5, or +6. In some embodiments, the metal(s) of the complex have a coordination number of 4 to 8.

[0242] In some embodiments, the metal(s) are one of the elements from groups 3, 4, 6, 7, 9, 10, 11, 13, 15, lanthanide elements, or actinide elements of the periodic table. The groups are assigned according to current IUPAC conventions and their old names In terms of terminology, Group 3 refers to the "Scandium Group" (IIIA), Group 4 to the "Titanium Group" (IVA), Group 6 to the "Actinide Group", Group 7 to the "Manganese Group", Groups 9, 10, and 11 (including the "Lanthanide Group"), Group 13 to the "Boron Group", and Group 15 to the "Nitrogen Group".

[0243] In some embodiments, the metal(s) are metallic radionuclides. Radionuclides, or radioactive nuclides, are atoms with unstable nuclei that undergo radioactive decay, emitting gamma rays or positrons, alpha or beta particles, or subatomic particles such as Auger electrons. These emissions constitute ionizing radiation. Radionuclides can occur naturally or be artificially created. Radionuclides are often called radioactive isotopes or radioisotopes.

[0244] In some embodiments, the metal(s) are: 89 Zr (diagnosis), 90 Nb (diagnosis), 90 Y (treatment), 153 Sm (treatment), 161 Tb (treatment), 177 Lu (treatment), 213 Bi (treatment) and 225 Selected from Ac (treatment). In some embodiments, metal(s) are, 89 Zr and 90 Selected from Nb. In some embodiments, the metal(s) are 90 Y, 153 Sm, 161 Tb, 177 Lu, 213 Bi and 225 Selected from Ac.

[0245] In some embodiments, the complex contains two different metals, one of which is a plurality of metals. 89 The second metal is Zr, 225 Ac or 177 Lu, preferably 177 Lu is preferable.

[0246] Typically, the metal coordinating with the first chelate ligand is a metal with substantially no affinity for binding to polyaminocarboxylic acid-type ligands, such as DOTA, DOTAGA, or NETA. In some embodiments, the complex is coordinated with the first chelate ligand, Zr (e.g., 89 Zr) and Nb (for example) 90A metal selected from Nb, preferably Zr.

[0247] Typically, the metal coordinating with the second chelate ligand is a metal with substantially no affinity for binding to polyhydroxamic acid-type ligands, such as DFOB. In some embodiments, the complex coordinates with the second chelate ligand, Y (e.g., 90 Y), Sm (for example) 153 Sm), Tb (for example) 161 Tb), Lu (for example) 177 Lu), Bi (for example) 213 Bi) and Ac (for example) 225 A metal selected from Ac, preferably Lu.

[0248] In some embodiments, the complex contains two different metals, preferably one of the metals is a radionuclide and the other is a naturally occurring, non-toxic metallic isotope. In some embodiments, one radionuclide coordinates with the binding site of a first chelate ligand in the compound, and one naturally occurring, non-toxic metallic isotope coordinates with the binding site of a second chelate ligand in the compound. In some embodiments, one naturally occurring, non-toxic metallic isotope coordinates with the binding site of a first chelate ligand in the compound, and one radionuclide coordinates with the binding site of a second chelate ligand in the compound. In some embodiments, the metal coordinating with the first chelate ligand is 89 The metal that coordinates with the second chelate ligand is Zr, which is non-toxic, naturally occurring Lu(III), i.e. nat Lu. In some embodiments, the metal coordinating with the first chelate ligand is a non-toxic, natural Zr(IV), i.e. nat The metal that coordinates with the second chelate ligand is Zr, 177 It is Lu. Both are in natural or radioactive nuclide forms that bind to one compound. nat Zr(IV) and nat Lu(III), or 89 Zr and 177 Lu, or 89 Zr and natLu(III), or nat Zr(IV) and 177 Any combination of a pair of different metals of Lu) nat Zr(IV) or 89 Zr is the It binds to the chelate ligand 1, nat Lu(III) or 177 Lu binds to a second chelate ligand, exhibiting identical pharmacokinetic and in vivo distribution characteristics, which is useful for search methods. nat Zr(IV) and nat Since Lu(III) is non-toxic to humans, this example should be useful.

[0249] Method for forming complexes In another embodiment of the present invention, a method for preparing the complex of the present invention is provided.

[0250] In some embodiments, a compound or a composition containing the compound is complexed with a metal. Preferably, the metal is a radionuclide. In some embodiments, a compound or a composition containing the compound is complexed with two different metals. Preferably, one or both of the different metals are radionuclides. Any complexing method known to those skilled in the art can be used to complex any of the compounds or compositions of the present invention.

[0251] In some embodiments, a compound or a composition containing a compound is made to form a complex with a single metal. In some embodiments, a compound or a composition containing a compound is made to form a complex with two different metals.

[0252] In some embodiments, the compound or composition is dissolved in water. 89 Zr(IV) and / or 177 A solution of radioactive nuclides (including multiple radionuclides) such as Lu(III) is added. In some embodiments, the radioactive nuclides (including multiple radionuclides) added are: 89 Zr(IV)(acac)4 and / or 177 It is a salt of a radioactive nuclide such as Lu(III)Cl3.

[0253] In some embodiments, a mixture comprising a compound or composition and radionuclides(s) is heated during the mixing of the compound and radionuclides. In some embodiments, the mixture is heated to over 25°C, over 30°C, over 35°C, over 37°C, over 40°C, over 50°C, over 60°C, over 70°C, or over 80°C. In some embodiments, the mixture is heated to about 37°C. In some embodiments, the mixture is heated to below 80°C, below 70°C, below 60°C, below 50°C, below 40°C, below 37°C, below 35°C, or below 30°C.

[0254] In some embodiments, a mixture containing a compound and radionuclides (including multiple radionuclides) is kept at ambient temperature (approximately 25°C) during the mixing of the compound and radionuclides (including multiple radionuclides).

[0255] In some embodiments, the mixture containing the compound and radionuclides(s) has heat-sensitive functionality, such as in antibodies, affibody, protein, peptide, or equivalent. In these embodiments, the mixture is preferably kept at about 37°C, at least below 37°C, or at ambient temperature (about 25°C) when the compound and radionuclides(s) are mixed.

[0256] In some embodiments, a mixture containing a compound and radionuclides(s) is cooled during the mixing of the compound and radionuclides(s). In some embodiments, the mixture is cooled to below about 25°C, below about 20°C, below about 15°C, or below about 10°C.

[0257] In some embodiments, one or more solutions containing a compound and a solution containing radionuclides (including multiple) are buffered.

[0258] Any method known to those skilled in the art can be used to measure radiochemical purity. For example, radiochemical purity may be measured using radioactive thin-layer chromatography (r-TLC) in a suitable solvent system. The solvent system depends on the specific compound being examined. For example, The r-TLC conditions described in Laria Patent Application No. 2011200132 may be applied to the compounds of the present invention.

[0259] Any method known to those skilled in the art can be used to separate the radiolabeled compound from the solution. For example, unwanted components can be removed using a resin, the solution containing the purified radiolabeled compound can be evaporated and dried, and then returned to the solution with water or buffer water for use. In some embodiments, the radiolabeled compound is separated by high-performance liquid chromatography (HPLC). In some embodiments, the radiolabeled compound is separated by solvent extraction or trituration.

[0260] Pharmaceuticals In a further embodiment, a pharmaceutical product is provided comprising the compound of the present invention and a complex of one nuclide with potential as a pharmaceutical.

[0261] In some embodiments, the pharmaceutical product comprises two radionuclides that have potential as pharmaceuticals.

[0262] In some embodiments, the pharmaceutical product comprises a complex of the compound of the present invention and one nuclide with pharmaceutically acceptable potential. In some embodiments, the pharmaceutical product comprises a complex of the compound of the present invention and two different nuclides with pharmaceutically acceptable potential, preferably one nuclide with pharmaceutically acceptable potential and a second nuclide with diagnostic potential.

[0263] In some embodiments, the pharmaceutical is a therapeutic agent, and at least one of a plurality of radionuclides has medicinal potential. In some embodiments, at least one of a plurality of radionuclides is a radionuclide with medicinal potential. Preferably, at least one of a plurality of radionuclides with medicinal potential is 90 Y, 153 Sm, 161 Tb, 177 Lu, 213 Bi and 225Selected from the group consisting of Ac. More preferably, at least one of several radionuclides with potential as pharmaceuticals is 177 Lu and 225 Selected from the group consisting of Ac. Much more preferably, at least one of several radionuclides with potential as pharmaceuticals is 177 It is Lu.

[0264] In some embodiments, the therapeutic agent is a diagnostic agent, and at least one of a plurality of radionuclides has diagnostic potential. In some embodiments, at least one of the plurality of radionuclides is a radionuclide with diagnostic potential. Preferably, at least one of the plurality of radionuclides with diagnostic potential is 89 Zr and 90 Selected from the group consisting of Nb. More preferably, at least one of several potentially diagnostic nuclides is selected. 89 Selected from the group consisting of Zr.

[0265] In some embodiments, the pharmaceutical is a theranostic drug, which comprises the compounds of the present invention and complexes of different nuclides that have potential as pharmaceuticals and potential for diagnostics.

[0266] In some embodiments, the drug is a radionuclide that may be used for prognosis diagnosis.

[0267] As used herein, the compounds, complexes, therapeutic agents, or compositions of the present invention may be used in a variety of applications, such as therapeutic agents, diagnostic agents, theranostic agents, or prognostic agents.

[0268] composition In a further embodiment, compositions comprising the compounds, complexes, or pharmaceuticals and pharmaceutically acceptable excipients of the present invention are provided.

[0269] A pharmaceutically acceptable excipient is typically a substance that is pharmaceutically inert, provides a transient or suitable form for a composition, and does not diminish the therapeutic or diagnostic effectiveness of the compound, complex, or pharmacopoeia. An excipient is generally considered “pharmaceutically acceptable” if, upon administration to a subject, it does not cause an unacceptable adverse, allergic, or other adverse reaction. The term “excipient” includes carriers or diluents.

[0270] The selection of pharmaceutically acceptable excipients tends to depend, at least in part, on the preferred route of administration. Generally, the compositions of this disclosure can be formulated for any route of administration, as long as the target tissue is available through that route. Compositions may be formulated from the compounds, complexes, or pharmaceuticals according to the present invention for any suitable route of administration, including, but not limited to, parenteral administration (including subcutaneous, intraperitoneal, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, subarachnoid, intraocular, periorbital, orbital, synovial, and intraperitoneal injection, intracisional injection, and any other similar administration or infusion techniques), infusion, or indwelling techniques (e.g., sterile, injectable aqueous or non-aqueous or suspension solutions).

[0271] Examples of components are described in Martindale, *The Extra Pharmacopoeia* (Pharmaceutical Press, London 1993), and Remington, *The Science and Practice of Pharmacy*, 21st Ed., 2005, Lippincott Williams & Wilkins. All methods involve the step of associating an active ingredient, such as a compound of the present invention, a pharmaceutical, or a complex, with one or more pharmaceutically acceptable excipients constituting minor components. Generally, compositions are prepared by uniformly and intimately associating an active ingredient, such as a compound of the present invention, a pharmaceutical, or a complex, with a dissolved additive, a liquid additive, or both. The composition contains an amount sufficient to produce the target compound, pharmaceutical, or complex to produce the desired effect. In some embodiments, the composition is formulated for intravenous use.

[0272] In some embodiments, the compositions of the present invention may be used as injectable preparations. Compositions intended for injection may be prepared by any known method, and such compositions may contain one or more agents selected from the group consisting of solvents, co-solvents, solubilizers, wetting agents, suspending agents, emulsifiers, thickeners, chelating agents, antioxidants, reducing agents, antimicrobial preservatives, buffering agents, pH adjusters, volume extenders, protective agents, osmotic pressure adjusters, and special additives. Furthermore, other non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of injectable preparations may be used.

[0273] The aqueous suspension may contain an active compound in a mixture with additives suitable for the manufacture of the aqueous suspension. Such additives are suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and acacia gum, and the dispersant or wetting agent may be a naturally occurring phosphatide such as lecithin, or a condensation product of an alkylene oxide and a fatty acid such as polyoxyethylene stearate, or a condensation product of an ethylene oxide and a long-chain aliphatic alcohol such as heptadecaethyleneoxyethanol, or a condensation product of an ethylene oxide and a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of an ethylene oxide and a partial ester derived from a fatty acid and hexitol anhydride such as polyethylene sorbitan monooleate. The aqueous suspension may also contain one or more colorants.

[0274] The pharmaceutical composition may be in the form of a sterile aqueous or oily suspension for injection. The preparation may be formulated by known methods using a suitable dispersant or wetting agent and suspension agent. The sterile injectable preparation may also be a sterile injectable solution or suspension of a non-toxic, parenterally acceptable diluent or solvent, such as a solution of 1,3-butanediol. Acceptable diluents or solvents that can be used include water, water for injection (SWFI), Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixatives are conveniently used as solvents or suspension media. For this purpose, any mild fixative may be used with synthetic mono or diglycerides. Furthermore, fatty acids such as oleic acid are used in the preparation of the injectable preparation.

[0275] In the context of this specification, the term “administer,” and variations thereof including “administer” and “give,” include contacting, applying, delivering, or providing the compounds, pharmaceuticals, complexes, or compositions of the present invention to a living organism or surface by any suitable means.

[0276] For the treatment or diagnosis of diseases or disorders, such as neoplastic diseases, the dosage of the bioactive compounds, pharmaceuticals, or complexes according to the present invention may be varied widely and adjusted to the individual's needs. The active compounds, pharmaceuticals, or complexes according to the present invention are generally administered in therapeutic or diagnostically effective doses. The usual dose may be administered as a single dose or in multiple doses. The amount of active ingredient that can be combined with additive materials to produce a single dosage form varies depending on the target being treated and the specific method of administration.

[0277] However, it is understood that a specific dosage for any particular subject depends on a variety of factors, including the activity of the specific compound, drug, or complex used, the subject's age, weight, general health, sex, and diet, the time of administration, the route of administration, and the rate of excretion, combination therapy (i.e., the use of other drugs to treat or diagnose the subject), and the severity of the specific disease being treated. Such treatment may be administered in as much as necessary and for as long as the treating physician deems necessary. Those skilled in the art will understand that the dosage plan or therapeutic or diagnostic effective dose of the compound, drug, or complex to be administered in the present invention may need to be optimized for each individual. They will also understand that different dosages may be required to treat or diagnose different diseases.

[0278] The terms “to treat,” “treatment,” and “therapy” are used herein to refer to curative and prophylactic treatments. Therefore, in the context of this disclosure, the term “to treat” includes treating, relieving, or alleviating the severity of a disease or disorder, such as neoplastic diseases and / or related diseases or symptoms of such diseases.

[0279] "Prevention" or "prevention" means preventing the onset of a disease or disorder such as a neoplastic disease, or, if a neoplastic disease occurs after administration of the compound or pharmaceutical composition of the present invention, mitigating the severity of the neoplastic disease.

[0280] The term "subjects" includes all humans and non-human animals. Therefore, in addition to being useful in the treatment of humans, the compounds of the present invention may also be useful in the veterinary treatment of mammals, including companion animals and livestock, such as but not limited to dogs, cats, horses, cows, sheep, and pigs.

[0281] The compound, pharmaceutical, or complex of the present invention may be administered together with the additives described above.

[0282] The pharmaceutical product of the present invention may be one or more radiolabeled scintigraphy or PET contrast agents. Radiolabeled scintigraphy or PET contrast agents having a suitable amount of radioactivity are also provided by this disclosure. When forming a radioactive complex for diagnostic purposes, it is generally preferred to form the radioactive complex in a solution containing radioactivity at a concentration of about 0.01 millicuries (mCi) / mL to 100 mCi / mL. Generally, the unit dose administered has a radioactivity of about 0.01 mCi to about 100 mCi, specifically about 1 mCi to about 30 mCi. The volume of the solution for a given dose is approximately 0.01 mL to 10 mL. The appropriate amount of radiolabeled conjugate for administration depends on the distribution profile of the selected conjugate, meaning that conjugates that are rapidly eliminated may need to be administered at a higher dose than those that are not rapidly eliminated. In vivo distribution and localization can be tracked at appropriate time points after administration, typically 30 minutes to 180 minutes, or for longer periods such as 3 to 4 days, depending on the accumulation rate at the target site relative to the clearance rate in non-target tissue, using standard scintigraphy / PET contrast methods. In vivo distribution and localization can be tracked using standard methods at time points less than 4 days, less than 3 days, less than 2 days, less than 1 day, less than 18 hours, less than 12 hours, less than 10 hours, less than 8 hours, less than 6 hours, less than 4 hours, less than 3.5 hours, less than 3 hours, less than 2.5 hours, less than 2 hours, less than 1.5 hours, less than 1 hour, or less than 45 minutes after administration. In vivo distribution and localization can be tracked using standard methods at the following time points: over 30 minutes, over 45 minutes, over 1 hour, over 1.5 hours, over 2 hours, over 2.5 hours, over 3 hours, over 3.5 hours, over 4 hours, over 6 hours, over 8 hours, over 10 hours, over 12 hours, over 18 hours, over 1 day, over 2 days, or over 3 days after administration. In vivo distribution and localization can be tracked using standard methods at the following time points: 30 minutes to 4 days, 30 minutes to 3 days, 30 minutes to 2 days, 30 minutes to 1 day, 30 minutes to 18 hours, 30 minutes to 12 hours, 30 minutes to 10 hours, 30 minutes to 8 hours, 30 minutes to 6 hours, 30 minutes to 4 hours, or 30 minutes to 3 hours after administration.

[0283] In a modified form, the present invention relates to a pharmaceutical composition. The pharmaceutical composition may contain pharmaceutically acceptable salts, solvates and their prodrugs, and may contain additives or other substances necessary to enhance the bioavailability or extend the lifespan of the compounds of the present invention.

[0284] The pharmaceutical composition containing the compound of the present invention may be in a form suitable for injection by the pharmaceutical composition itself or by using liposome (mCi) micelles and / or nanoparticles.

[0285] The solution of the present invention may be provided in a sealed container, particularly a glass container, in either a single dosage form or multiple dosage forms.

[0286] Any pharmaceutically acceptable salt of any of the compounds, complexes, or pharmaceuticals described herein may be used to prepare the solutions of the present invention. Suitable salts may include, for example, salts with mineral-containing inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like, as well as salts with certain organic acids such as acetic acid, succinic acid, tartaric acid, ascorbic acid, citric acid, glutamic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid and the like.

[0287] Any pharmaceutically acceptable solvent capable of dissolving the compounds, complexes, or pharmaceuticals described herein or their pharmaceutically acceptable salts may be used. The solutions of the present invention may also contain one or more additional components, such as a co-solubilizing agent (which may be the same as the solvent), an osmotic regulator, a stabilizer, a preservative, or a mixture thereof. Examples of solvents, co-solubilizing agents, osmotic regulators, stabilizers, and preservatives suitable for solution formulations are described below.

[0288] Suitable solvents and co-solubilizing agents include water, water for injection (SWFI), physiological saline, alcohols such as ethanol, benzyl alcohol and similar substances, glycols and polyalcohols such as propylene glycol, glycerin and similar substances, polyalcohol esters such as diacetin, triacetin and similar substances, polyglycols and polyethers such as polyethylene glycol 400, polyethylene glycol methyl ether and similar substances, dioxolanes such as isopropylidene glycerin and similar substances, dimethyl isosorbide, etc., 2-pyrrolidone, N-methyl-2-pyrrolidone, polyvinylpyrrolidone (co-solubilizing agent). Examples include, but are not limited to, pyrrolidone derivatives (solubilizer only) and similar substances; polysorbates such as polyoxyethylene-containing fatty alcohols, esters of polyoxyethylene-containing fatty acids, and Tween™; and polyoxyethylene derivatives of polypropylene glycol such as Pluronic™.

[0289] Suitable osmotic regulators include, but are not limited to, pharmaceutically acceptable inorganic chlorides such as sodium chloride, glucose, lactose, mannitol, sorbitol, and similar substances.

[0290] Suitable preservatives for physiological administration may include, for example, p-hydroxybenzoic acid esters (e.g., methyl, ethyl, propyl, and butyl esters, or mixtures thereof), chlorocresol, and similar substances.

[0291] In some embodiments, the formulation may also include a radioprotective agent. Examples of such additives include, but are not limited to, gentisic acid and L-ascorbic acid or a combination thereof.

[0292] Suitable stabilizers include, but are not limited to, monosaccharides (e.g., galactose, fructose, and fucose), disaccharides (e.g., lactose), polysaccharides (e.g., dextran), cyclic oligosaccharides (e.g., α-, β-, γ-cyclodextrins), aliphatic polyols (e.g., mannitol, sorbitol, and thioglycerol), cyclic polyols (e.g., inositol), and organic solvents (e.g., ethyl alcohol and glycerol).

[0293] The solvents and co-solubilizers, osmotic pressure regulators, stabilizers, and preservatives described above may be used individually or as a mixture of two or more of them in the solution formulation.

[0294] In some embodiments, the pharmaceutically acceptable solvent formulation may contain a compound, complex, or pharmaceutical product described herein or a pharmaceutically acceptable salt thereof, and an agent selected from the group consisting of sodium chloride solution (i.e., physiological saline), glucose, mannitol, or sorbitol, in an amount of 5% or less. The pH of such formulation may also be adjusted to improve storage stability using a pharmaceutically acceptable salt or base.

[0295] In the solution of the present invention, the concentration of the compound, complex, or pharmaceutical product described herein, or a pharmaceutically acceptable salt thereof, may be less than 100 mg / mL, less than 50 mg / mL, less than 10 mg / mL, or less than 5 mg / mL but greater than 0.01 mg / mL, or between 0.5 mg / mL and 5 mg / mL, or between 1 mg / mL and 3 mg / mL. In some embodiments, the concentration used is an ideal concentration that is sufficiently cytotoxic to cancer cells but has limited toxicity to other cells.

[0296] Suitable packaging for pharmaceutical solution formulations may be any approved container intended for parenteral use, such as plastic and glass containers, ready-to-use syringes and similar items. In some embodiments, the container is a sealed glass container, such as a vial or ampoule. Hermetically sealed glass vials are particularly preferred.

[0297] In one embodiment, the packaging may include cGMP / cGLP / cGCP / cGPvP as packaging.

[0298] According to embodiments of the present invention, a sterile injection of the complex, pharmaceutical and composition described herein or a pharmaceutically acceptable salt thereof into a physiologically acceptable solvent is performed in a sealed glass container. A possible solution is provided, the solution having a pH of 2.5 to 3.5. In some embodiments, the complex, pharmaceutical, or composition of the present invention comprises two different radionuclides, preferably one radionuclide having pharmaceutical potential and the other radionuclide having diagnostic potential. The complex, pharmaceutical, and composition comprising one radionuclide is preferably bound to either a first chelate ligand or a second chelate ligand. 89 Complexes, pharmaceuticals, and compositions containing Zr are preferably bound to a first chelate ligand. 89 Complexes, pharmaceuticals, and compositions containing radionuclides other than Zr are preferably bound to a second chelate ligand. Complexes, pharmaceuticals, and compositions containing two different radionuclides are 89 Zr binds to the first chelate ligand, 89 It is preferable that a radionuclide other than Zr binds to the second chelate ligand. A complex, pharmaceutical, and composition comprising one or more radionuclides, two different radionuclides, and one or more proteins, peptides, antibodies, and nanoparticles is preferred. The first chelate ligand is bound to... 89 One radionuclide such as Zr or 89 A complex, pharmaceutical, and composition comprising a radionuclide bound to a second chelate ligand other than Zr, and one or more proteins, peptides, antibodies, and nanoparticles is preferred. 89 Zr and the second chelate ligand are bound together. 89Preferred are complexes, pharmaceuticals, and compositions comprising two different radionuclides, such as radionuclides other than Zr, and one or more proteins, peptides, antibodies, and nanoparticles. For solution formulations, the nuclide compounds of the present invention may be more soluble and stable for extended periods in solutions with a pH of less than 6. In one embodiment, the pH of the biomolecule (protein, peptide, or antibody) conjugated with the radionuclide should be in the range of 6.5 to 7, suitable for injection into an individual (e.g., a human). Furthermore, the salts of the compounds of the present invention may be more soluble in aqueous solutions than their free base counterparts; however, when the salt is added to an aqueous solution, the pH of the solution may be too low to be suitable for administration. Therefore, solution formulations with a pH greater than 4.5 can be combined before administration with a dilution solution with a pH greater than 7 such that the pH of the combined formulation to be administered is 4.5 or higher. In one embodiment, this dilution solution contains a pharmaceutically acceptable base such as sodium hydroxide. In another embodiment, this dilution solution has a pH of 10 to 12. In another embodiment, the pH of the combined formulation to be administered is greater than 5.0. In another embodiment, the pH of the administered combined formulation is pH 5.0 to 7.0.

[0299] The present invention also provides a process for preparing a sterile solution with a pH of 2.5 to 3.5, which involves dissolving a compound, complex, pharmaceutical or composition described herein, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable solvent. When using a pharmaceutically acceptable salt of a compound, complex, pharmaceutical or composition described herein, the pH of the solution may be adjusted using a physiologically acceptable acid or a pharmaceutically acceptable base or basic solution to which a buffer is added to adjust the pH to a desired range. This method may further include passing the resulting solution through a sterile filter.

[0300] In some embodiments, the compounds, pharmaceuticals, complexes, or compositions of the present invention may be administered in combination with additional active ingredients (APIs). The APIs may be any radionuclides with potential pharmaceutical properties that are suitable for treating or diagnosing any disease, condition, and / or disorder, such as neoplastic diseases. The compounds, pharmaceuticals, complexes, or compositions of the present invention may be formulated simultaneously with additional APIs and any of the pharmaceutical compositions described herein, or the compounds, pharmaceuticals, complexes, or compositions of the present invention may be administered simultaneously, sequentially, or individually. Simultaneous administration includes administering the compounds, pharmaceuticals, complexes, or compositions of the present invention together with other APIs, whether formulated simultaneously or in separate dosage forms, via the same or different routes. Sequential administration includes administering the compounds, pharmaceuticals, complexes, or compositions of the present invention and other APIs via the same or different routes, according to separate dosing schedules, such as within about 0.5 hours, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours of each other. When administered sequentially, the compounds, pharmaceuticals, complexes, or The composition may be administered before or after the administration of other APIs. Individual administration involves administering the compounds, pharmaceuticals, complexes, or compositions of the present invention and other APIs according to separate administration plans, via any route suitable for any of the active ingredients, which may be the same or different.

[0301] This method may involve administering the compound, pharmaceutical, complex, or composition of the present invention in any pharmaceutically acceptable form. The pharmaceutical composition may contain any pharmaceutically acceptable excipient described herein.

[0302] The compounds, pharmaceuticals, complexes, or compositions of the present invention may be administered parenterally by any suitable method, such as subcutaneous, intraperitoneal, intravenous, intramuscular, or intracisional administration, injection, or indwelling techniques (e.g., sterile, injectable aqueous solutions, non-aqueous solutions, or suspensions).

[0303] The compounds, pharmaceuticals, or complexes of the present invention may be provided as any of the pharmaceutical compositions described herein.

[0304] Treatment method Any of the compounds, complexes, compositions, and agents described herein may be used to treat any disease or condition treatable with a potentially pharmaceutically acceptable nuclide that has complexed with this compound prior to administration.

[0305] Radionuclides are typically used to treat neoplastic diseases, including cancer, and treatment with radionuclides can be considered internal radiotherapy.

[0306] Accordingly, a method for treating a neoplastic disease is provided, comprising administering a therapeutically effective amount of the complex of the present invention to a subject requiring treatment for the neoplastic disease. The complex may be administered in the form of a pharmaceutical or pharmaceutical composition. Any suitable agent or composition described herein may be used.

[0307] The complex of the present invention may be any of the complexes described herein, and this nuclide may have pharmaceutical potential. The complex may be in the form of a pharmaceutical or pharmaceutical composition of the present invention. The complex may further contain a nuclide that has diagnostic potential such that the therapeutic method is also a diagnostic method.

[0308] This method may further include the step of contacting the compound or composition of the present invention with a potentially therapeutic metal to form the complex of the present invention.

[0309] In a further embodiment, the use of the complex of the present invention in the manufacture of drugs for the treatment of neoplastic diseases is provided.

[0310] In a further embodiment, the use of the compounds of the present invention in the manufacture of drugs for the treatment of neoplastic diseases is provided, the drugs comprising compounds that have formed complexes with radionuclides of potential pharmaceutically acceptable properties.

[0311] In a further embodiment, the use of a potentially pharmaceutically acceptable nuclide in the manufacture of a drug for the treatment of neoplastic diseases is provided, the drug comprising a compound that has complexed with the potentially pharmaceutically acceptable nuclide.

[0312] In a further embodiment, the use of the complex of the present invention in the treatment of neoplastic diseases is provided.

[0313] In a further embodiment, the present invention provides a complex for use in the treatment of neoplastic diseases. It will be done.

[0314] In some embodiments of the present invention, the complex incorporates a target moiety that directs the compound to a target tissue, organ, receptor, or other biologically expressed composition to enable targeted delivery of the nuclide to cancer. In some embodiments of the present invention, the complex incorporates the target moiety girentuximab.

[0315] In some embodiments, radionuclides with potential as pharmaceuticals are, 90 Y, 153 Sm, 161 Tb, 177 Lu, 213 Bi and 225 Ac, preferably 177 Lu and 225 Acous more 177 Selected from Lu.

[0316] In some embodiments, the complex further includes radionuclides of diagnostic potential, the radionuclides of diagnostic potential are: 89 Zr is a radionuclide with therapeutic potential, 225 Ac or 177 Lu, preferably 177 It is Lu.

[0317] Neoplastic diseases include malignant and benign cancerous growths. In some embodiments, the treatment is for cancer. In some embodiments, the treatment is for cancer having an alloantigen. In some embodiments, the treatment is for cancer selected from the group consisting of prostate cancer, including castration-resistant metastatic prostate cancer; breast cancer; renal cancer, including metastatic clear cell renal cell carcinoma; pancreatic cancer; lung cancer; gastric cancer; or metastatic bone disease. In some embodiments, the treatment is for prostate cancer, such as castration-resistant metastatic prostate cancer. In some embodiments, the treatment is for breast cancer. In some embodiments, the treatment is for pancreatic cancer. In some embodiments, the cancer having an alloantigen is PSMA, and the cancer is selected from the group consisting of prostate tumors or cells, metastatic prostate tumors or cells, lung tumors or cells, renal tumors or cells, glioblastoma, pancreatic tumors or cells, bladder tumors or cells, sarcoma, melanoma, mammary gland tumors or cells, colon tumors or cells, germ cells, pheochromocytoma, esophageal tumors or cells, gastric tumors or cells, and combinations thereof. In some embodiments, the cancer possessing the same antigen is carbonic anhydrase IX, and the cancer is metastatic clear cell renal cell carcinoma.

[0318] In some embodiments, cancer is diagnosed in vitro, in vivo. This is either in vivo or ex vivo. In certain embodiments, cancer is present in the subject.

[0319] In animals, "cancer" refers to the presence of cells that possess characteristics representative of cancerous cells, such as uncontrolled proliferation, reduced specific functions, immortality, significant metastatic potential, significantly increased anti-apoptotic activity, rapid growth and proliferation rates, and specific characteristic morphology and cellular markers. In some situations, cancer cells take the form of a tumor, and such cells may exist locally within the animal body or circulate in the bloodstream like independent cells.

[0320] As used herein, the term “effective dose” refers to the amount of a drug or pharmaceutical product that elicits a biological, physical, or medical response in a tissue, system, animal, or human, for example, as sought by a researcher or clinician. Furthermore, the term “therapeutic effective dose” refers to any amount that, compared to a corresponding subject who has never received such a dose, causes treatment, cure, prevention, or remission of a disease, improvement of side effects, or a reduction in the rate of progression of a disease or disability. This term also includes amounts that are effective in enhancing normal physiological function within the scope of the term. Furthermore, the term “diagnostic effective dose” refers to any amount that, compared to a corresponding subject who has never received such a dose, causes improvement in the diagnosis, imaging, or assessment of a health condition, or causes the likely performance of a subject, organ, or tissue.

[0321] Diagnostic methods In a further embodiment, the present invention provides a diagnostic method for a subject requiring diagnosis, the method comprising administering to the subject a diagnostically effective amount of a complex containing the compound of the present invention and a potentially diagnostic nuclide.

[0322] This complex may be a complex of any of the compounds of the present invention and any of the diagnostically possible radionuclides described herein. This complex may further contain a radionuclide that has therapeutic potential, such that this diagnostic method is also a therapeutic method.

[0323] This method may further include the step of contacting the compounds and compositions of the present invention with a potentially diagnostic metal to form the complexes of the present invention.

[0324] In a further embodiment, the use of the complex of the present invention in the manufacture of drugs for the diagnosis of neoplastic diseases is provided.

[0325] In a further embodiment, the invention provides a use of the compound in the manufacture of a drug for the diagnosis of neoplastic diseases, wherein the drug comprises the compound and a complex of a potentially diagnostic nuclide.

[0326] In a further embodiment, the use of a diagnostically possible radionuclide in the manufacture of a drug for the diagnosis of neoplastic diseases, wherein the drug comprises the compound and a complex of the diagnostically possible radionuclide.

[0327] In a further embodiment, the present invention provides a complex for use in the diagnosis of neoplastic diseases.

[0328] In some embodiments of the present invention, the complex incorporates a target moiety that directs the compound to a target tissue, organ, receptor, or other biologically expressed composition, enabling targeted delivery of this nuclide to cancer. In some embodiments of the present invention, the complex incorporates the target moiety girentuximab.

[0329] In some embodiments, the radionuclides with diagnostic potential are radionuclides suitable for PET contrast imaging, and preferably 89 Zr and 90 Selected from Nb, most preferably 89 It is Zr. In some embodiments, the diagnostically possible nuclide is a nuclide suitable for MRI, preferably Gd.

[0330] In some embodiments, the complex further includes radionuclides of potential therapeutic properties, and the radionuclides of potential diagnostic properties are: 89 Zr is a radionuclide with potential therapeutic properties. 225 Ac or 177 Lu, preferably 177 Lu is preferable.

[0331] In some embodiments, the diagnostic method includes subjecting the subject to positron emission tomography (PET) contrast imaging, preferably immunoPET imaging. PET imaging is a functional imaging technique applied in nuclear medicine that creates three-dimensional images of living organisms (e.g., functional processes). The system detects pairs of gamma rays indirectly emitted by positron-emitting radionuclides, which are introduced into the body in the form of pharmaceutical compounds.

[0332] In some embodiments, this diagnostic method involves subjecting the subject to magnetic resonance imaging (MRI), and the possible diagnostic radionuclide is Gd.

[0333] In some embodiments, this diagnosis is for neoplastic diseases. In some embodiments, this diagnosis is for cancer. The diagnostic method is for any of the cancers described herein. It may be applied for therapeutic purposes. The compounds and compositions of the present invention may be applied for therapeutic or diagnostic purposes depending on the selection of a chosen metal that forms a complex with them.

[0334] In some embodiments, the diagnostic method of the present invention may be used in combination with other diagnostic methods such as magnetic resonance imaging (MRI), radiography, ultrasound imaging, elastography, photoacoustic imaging, tomography (including computed tomography), and echocardiography, preferably magnetic resonance imaging (MRI) and tomography (including computed tomography).

[0335] Manufacturing method In a further embodiment, a method for producing the compound or composition of the present invention is provided.

[0336] Typically, the compounds or compositions of the present invention may be prepared by techniques known in the art. The specific reagents and conditions for bringing each of these steps to fruition depend on the specific substituents selected for each reaction partner. Those skilled in the art will readily understand how to determine and / or optimize these reagents and conditions. Similarly, if the starting materials are not commercially available, those skilled in the art will be able to design and carry out methods for preparing the starting materials based on the techniques and reactions described above. Embodiments of these steps are provided in the examples with reference to specific compounds described herein.

[0337] The reagents for preparing the compounds of the present invention can be obtained from any source. Various sources are known to those skilled in the art. The reagents may be synthetic or obtained from natural sources. The reagents may be of any purity, and may be separated and purified, for example, using any technique known to those skilled in the art.

[0338] Any method known to those skilled in the art can be used to form a chelate ligand moiety, linker moiety, target moiety, substituent capable of forming a conjugate with the target moiety, or substituent moiety with a suitable moiety of the compound. The reaction may be carried out in an aqueous or non-aqueous medium. Reagents may be used in any ratio in the reaction mixture. The reaction product may be used immediately, stored, or further treated to enhance stability before storage by processes such as lyophilization.

[0339] In some embodiments, the bond between one or more chelate ligands and a linker group, or, if the linker is a bond, between two different chelate ligands, is an amide bond. Any method known in the art can be used to form an amide bond. Preferred amide bond-forming reagents include those proceeding with mixtures of carboxylic acid and carbonic acid anhydrides (e.g., PivCl, Boc2O, and EEDQ), those proceeding with sulfonic acid anhydrides (e.g., TsCl), those proceeding with phosphoric acid anhydrides (e.g., T3P), activated esters (e.g., NHS), carbodiimides (e.g., DCC and EDC), guanidine and uranium salts (e.g., HBTU and TPTU), triazine reagents (e.g., cyanuryl chloride), and boron species (e.g., boric acid). Amide bond-forming reagents proceeding with activated esters (e.g., NHS), carbodiimides (e.g., DCC and EDC), and guanidine and uranium salts (e.g., HBTU and TPTU) are particularly preferred. NHS, EDC, and HBTU are particularly preferred amide bond-forming reagents.

[0340] In one embodiment, A-COOH and H2NL under amide bond formation conditions. 1The compound of the present invention is formed by a reaction between -COOH and then the reaction of the product formed under amide bond formation conditions with H2N-B. L 1 L 1 This is the portion of linker L that does not contain the amine and carboxylic acid groups shown.

[0341] In one embodiment, H2N-B and H2NL under amide bond formation conditions. 1 -COOH The compound of the present invention is formed by the reaction between the intermediate reaction and the subsequent reaction of the product produced under amide bond formation conditions with A-COOH. L 1 L 1 This is the portion of linker L that does not contain the amine and carboxylic acid groups shown.

[0342] In one embodiment, HOOC-B and H2NL under amide bond formation conditions. 1 The compound of the present invention is formed by a reaction between -COOH and then a reaction between the product formed under amide bond formation conditions and A-NH2. L 1 L 1 This is the portion of linker L that does not contain the amine and carboxylic acid groups shown.

[0343] In one embodiment, A-NH and H2NL under amide bond formation conditions. 1 The compound of the present invention is formed by a reaction between -COOH and the product generated under amide bond formation conditions, followed by a reaction between the product and HOOC-B. L 1 L 1 This is the portion of linker L that does not contain the amine and carboxylic acid groups shown.

[0344] In one embodiment, the compound of the present invention is formed by a reaction between A-NH and HOOC-B.

[0345] In one embodiment, the compound of the present invention is formed by a reaction between A-COOH and HN-B.

[0346] Any method known to those skilled in the art can be used to purify the compound or composition of the present invention. In some embodiments, the compound or composition is purified by solvent extraction or trituration. In some embodiments, the compound or composition is purified by liquid chromatography, high-performance liquid chromatography (HPLC), molecular sieve chromatography (gel permeation chromatography), affinity chromatography, or ion exchange chromatography. In some embodiments, the compound or composition is purified by high-performance liquid chromatography (HPLC). In some embodiments, the compound or composition is separated by high-performance liquid chromatography (HPLC).

[0347] The compounds, compositions, kits, and methods described herein are illustrated by the following exemplary and non-exclusive examples.

[0348] The inventions disclosed and defined herein are understood to encompass all alternative combinations of two or more individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative embodiments of the invention.

[0349] The methods and compounds described herein are illustrated by the following exemplary and non-exclusive examples. [Examples]

[0350] General comments on synthesis The synthesis of the two-component system (DFOB-DOTA(2)), the three-component system (DFOB-L-LYS-DOTA(3)), and the four-component system (DFOB-PPH-L-LYS-DOTA(4)) requires the formation of one, two, or three amide bonds, respectively. Amide bond formation chemistry can be carried out using various methods. In one method, the carboxylic acid-containing motif can be activated with N-hydroxysuccinimide (NHS) and reacted with the amine-containing fragment in the presence of a base. In this chemistry, the NHS-activated component must first be separated before the next reaction. In another route, N,N,N′,N′-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluoro The carboxylic acid group can be activated in situ using phosphate (HBTU), and then the amine-containing fragment can be directly introduced into the mixture in the presence of a base. This is advantageous because the reaction can be carried out in one step (i.e., a "one-pot" reaction). The NHS pathway was used to prepare the two-component system (DFOB-DOTA(2)). The HBTU pathway was used to prepare the three-component system (DFOB-L-LYS-DOTA(3)) and the four-component system (DFOB-PPH-L-LYS-DOTA(4)).

[0351] Utensil use Mass spectra were acquired using a reversed-phase liquid chromatography-mass spectrometry system equipped with an automated injection system (100 μL loop), an Agilent 1260 Infinity degasser, a quaternary pump, and an Agilent 6120 series quadrupole electrospray ionization (ESI) mass spectrometer. All experiments used an Agilent C18 reversed-phase packed column (4.6 × 150 mm inner diameter, 0.5 mL min). ‐1A particle size of 5 μm was used. The following instrument conditions were used: 5 μL injection volume, 4 kV spray voltage, 3 kV capillary voltage, 250 °C capillary temperature, and 10 V tube lens offset. The mobile phase was prepared by mixing acetonitrile:formic acid (99.9:0.1) (ACN:FA) and H2O:formic acid (99.9:0.1). In this method, a flow rate of 0.5 mL min over 40 minutes was used as required. ‐1 Alternatively, a flow rate of 0.8 mL min over 25 minutes. ‐1 A 5-95% ACN:H2O gradient was used. Spectral data were acquired and processed using the Agilent OpenLAB Chromatography Data System ChemStation Edition. Preparative high-performance liquid chromatography (HPLC) was performed on a Shimadzu LC-20 series LC system equipped with two LC-20AP pumps, a SIL-10AP autosampler, an SPD-20AUV / VIS detector, and an FRC-10A fraction collector. For semi-preparative purification, a flow rate of 20 mL min was used. ‐1 A Shimadzu Shimpack GIS column (150 × 20 mm inner diameter, 5 μm particle size) was used. The organic phase (B) consisted of ACN:TFA (99.95:0.05). The aqueous phase (A) consisted of H2O:TFA (99.95:0.05). Spectral data was acquired and processed using Shimadzu LabSolutions Software (version 5.73).

[0352] material DOTA tri(tert-butyl) ester (1b) (97%) was obtained from Arctom Chemicals. N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (99%) was obtained from Chem-Impex. Acetonitrile-190, toluene (≧99.5%), aqueous ammonia (28%), and diethyl ether were obtained from Ajax Finechem. N-hydroxysuccinimide (98%), desferrioxamine B mesylate (≧92.5%) (1a), triethylamine (≧99%), trifluoroacetic acid (99%), triisopropylsilane (98%), N,N,N′,N′-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (≧98%) (HBTU), 1,4-phenylenediisothiocyanate (98%), sodium bicarbonate (≧99.7%), sodium sulfate (anhydrous, ≧99%), N,N-dimethylformamide (99.8%), piperidine (99%), sodium hydroxide (anhydrous, ≧98%), hydrochloric acid (37%), lutetium chloride (99.9%), zirconium chloride (≧99.9%), and zirconium acetylacetonate (98%) were obtained from Sigma-Aldrich. Milli-Q water was prepared using the Millipore Q-pod system. Fmoc-L-LYS-DOTA(O t Bu)3(1c) was obtained from Macrocyclics. N,N-diisopropylethylamine was obtained from Sigma-Aldrich (99.5%) and Merck (98%). Dichloromethane was obtained from Ajax Finechem and Merck. Methanol was obtained from Ajax Finechem and Chem-supply (≧99.9%). Ammonium acetate (≧97%) was obtained from APS Finechem. Girentuximab was obtained from Telix Pharmaceuticals Pty Ltd.

[0353] Example 1 Synthesis of DFOB-DOTA(2) The synthesis of DFOB-DOTA(2) is described in detail below. [ka]

[0354] DOTA tri(tert-butyl) ester (2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl)acetic acid) (359.6 mg, 0.63 mmol) (1b) is dissolved in DCM (35.8 mL), and N-hydroxysuccinimide (NHS) (108.3 mg, 0.94 mmol) was added, followed immediately by the addition of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (488.7 mg, 3.15 mmol). The mixture was stirred at ambient temperature for 16 hours. Water (35 mL) was added to the reaction solution, and after stirring, the organic layer was collected. The aqueous layer was further extracted with DCM (3 × 35 mL), and the organic layers were combined. The solvent was removed under vacuum (external bath, 45°C), and NHS-activated DOTA tri(tert-butyl) ester (tri-tert-butyl 2,2',2''-(10-(2-((2,5-dioxopyrrolidine-1-yl)oxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate) was obtained as a yellow oily substance. ESI-MSC 32 H 55 N5O 10 The calculated cations for [M+H] + 670.39.

[0355] A methanol solution (5 mL) of desferrioxamine B mesylate (134.4 mg, 0.20 mmol) (1a) was added to a MeOH solution (5 mL) of NHS-activated DOTA tri(tert-butyl) ester (212.8 mg, 0.32 mmol) and triethylamine (67 μL, 0.48 mmol). The resulting solution was stirred under reflux at 70°C for 3 hours. The solvent was removed under vacuum, the residue was washed with cold diethyl ether (3 × 10 mL), water (20 mL) was added, and the slurry was transferred to a 50 mL Falcon tube. This solid was separated by centrifugation and transferred to a round-bottom flask, after which all remaining solvent was removed under vacuum (external bath 45°C), thereby obtaining DFOB-DOTA tri(tert-butyl) ester as a white solid. ESI-MS C 53 H 98 N 10 O 15 The positive ions calculated for this: [M+H] + 1115.72.

[0356] DFOB-DOTA tri(tert-butyl) ester (179.7 mg, 0.16 mmol) was dissolved in a mixture of DCM:TFA:TIPS, 1.47 mL:5.13 mL:87 μL, and this solution was stirred at room temperature for 16 hours. The solvent was removed under vacuum (external bath at 45°C). Cold diethyl ether (10 mL) was added to the residue, and the product was extracted into the solvent phase. After transferring the slurry to a round-bottom flask, the remaining solvent was removed under vacuum (external bath at 45°C) to obtain the crude product as a white solid. This product was stirred at a flow rate of 20 mL min as follows. ‐1 The product was purified by HPLC using a stepwise gradient of mobile phase B in mobile phase A, with concentrations of 0-12% from 0-7.5 minutes, 12-22% from 7.5-17.5 minutes, and 22-40% from 17.5-20 minutes. The product was collected at 14.43 minutes, these fractions were pooled, and the solvent was removed by lyophilization to obtain DOTA-DFOB as a white solid (4.08 mg, 2.16%). Note: The exact yield could not be calculated. During lyophilization, the lyophilizer malfunctioned, resulting in a significant loss of material. Sufficient material was obtained for analysis. ESI-MS C 41 H74 N 10 O 15 The positive ions calculated for this: [M+H] + 947.53. See Figures 2a and 3a.

[0357] Example 2 Selective complex formation when DFOB-DOTA(2) is exposed to various metal ions. The selective metal complex formation of the single chelate ligand in the DFOB-DOTA(2) embodiment is described in detail below. [ka]

[0358] DFOB-DOTA(2) was mixed separately with solutions containing Zr(IV) and Lu(III). In both cases, ESI-MS analysis was consistent with the fact that only one of the two chelate ligands of DFOB-DOTA(2) complexed with the metal ion. The known chelate ligand affinities for Zr(IV) and Lu(III) are consistent with the fact that the two metals complexed with different chelate ligands of DFOB-DOTA(2). The inventors stated, 13 We predicted that 13C nuclear magnetic resonance (NMR) spectroscopy experiments would further confirm the chelate ligand selectivity of the metal-compound complex. Figures 2 and 3 show the LCMS and mass spectrometry results for Examples 2a and 2b.

[0359] Example 2a: Formation of Zr(IV)-DFOB-DOTA(Zr-2) A methanol-water (1:1) solution of Zr(acac)4 was added to a methanol-water (1:1) solution of DFOB-DOTA (8.65 equivalents). The mixture was stirred at ambient temperature for 22 hours. The solution was analyzed using LC-MS. 41 H 71 N 10 O 15 Positive ions calculated for Zr: [M] + 1033.4. Refer to Figures 2b and 3b.

[0360] Example 2b: Formation of Lu(III)-DFOB-DOTA(Lu-2) 249 μL of ammonium acetate solution of DOTA-DFOB (2.5 mM) was added to 62 μL of aqueous solution of LuCl3 (50 mM). The resulting 5:1 Lu(III):DFOB-DOTA(2) solution was stirred at 37°C for 2 hours and then at ambient temperature for 20 hours. The solution was analyzed using LC-MS. ESI-MSC 41 H 71 N 10 O 15 Positive ions calculated for Lu: [M+H] + 1119.5. See Figures 2c and 3c.

[0361] Example 3 Synthesis of DFOB-L-LYS-DOTA(3) [ka] DFOB-Fmoc-L-LYS-DOTA(O t Bu)3(3a) A sample of Fmoc-L-Lys-mono-amide-DOTA-tris(t-Bu ester) (92.1 mg, 86.1 μmol) was dissolved in N,N-dimethylformamide (DMF) (10 mL), and then N,N-diisopropylethylamine (DIPEA) (35 μL, 200.9 μmol) was added. This solution was stirred at room temperature (rt) for 10 minutes. N,N,N′,N′-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU) (45.3 mg, 119.4 μmol) was added to this solution, and it was stirred at room temperature for 30 minutes. Desferrioxamine mesylate (78.3 mg, 119.2 μmol) was added to this solution, and it was heated to 50°C and stirred for 1 hour. A certain volume of dichloromethane (DCM) (100 mL) was added to the reaction mixture, and the mixture was extracted three times with 50 mL aliquots of saturated sodium bicarbonate and once with 50 mL aliquots of brine. The organic layer containing the product was dried over anhydrous sodium sulfate, and after vacuum filtration, the solvent was removed under vacuum to obtain the semi-purified product tris(tBu)DOTA-(Fmoc)Lys-DFOB as a yellow oily substance. Crude yield = 102.7%. Comment: Fmoc-L-LYS-DOTA(O t The Bu)3)-OH(1c) skeleton was prepared in the laboratory using methods known in the art (see, for example, De Leon-Rodriguez et al (2004) Solid-phase synthesis of DOTA-peptides, Chem. - Eur. J. 10, 1149-115).

[0362] DFOB-L-LYS-DOTA(3) A sample of DFOB-Fmoc-L-Lys-mono-amide-DOTA-tris(t-Bu ester) (134.6 mg, 91.9 μmol) was suspended in piperidine:DMF (1:4, 0.4 mL:1.6 mL) and stirred at room temperature for 1 hour. The solvent was removed under vacuum, and the residue was dissolved in TFA:DCM (9:1,900 μL:100 μL) while stirring at room temperature for 16.5 hours. The solvent was removed under vacuum, and the remaining TFA was removed by sequential treatment (dissolution / vacuum removal) with methanol and then toluene. The oily residue was suspended in a minimum aliquot of water, and the pH of the solution was adjusted to 7 with an aliquot of 1 M NaOH or HCl. The solvent was removed under vacuum to give the oily residue, which was dissolved in H2O:acetonitrile (ACN) 7:3 for HPLC purification. The fraction containing DOTA-Lys-DFOB was collected, and the solvent was removed using a high-vacuum freeze-drying apparatus to obtain a white powder. Final yield (after HPLC purification): 40.5%.

[0363] C 47 H 86 N 12 O 16 The m / z value calculated for [M] is [M+H]. + 1075.6, [M+2H] 2+ 538.3, [M+3H] 3+ 359.2; measured values ​​1075.5, 538.4, 359.3. See Figures 4a and 5a.

[0364] Example 4 Selective complex formation of the three-component system DFOB-L-LYS-DOTA(3) upon exposure to various metal ions. The selective metal complex formation of the sole chelate ligand DFOB-L-LYS-DOTA(3) is described in detail below. [ka]

[0365] As described above, DFOB-L-LYS-DOTA(3) was mixed with solutions containing Zr(IV) and Lu(III) in separate experiments. In both cases, ESI-MS analysis was consistent with the fact that only one of the two chelate ligands of DFOB-L-LYS-DOTA(3) formed a complex with the metal ion. The known chelate ligand affinities for Zr(IV) and Lu(III) were consistent with the fact that the two metals formed complexes with different chelate ligands of DFOB-L-LYS-DOTA(3). Figures 4 and 5 provide the LCMS and mass spectrometry results for Examples 4a and 4b.

[0366] Example 4a: Formation of Zr(IV)-DFOB-L-LYS-DOTA(Zr-3) 249 μL of a 2.5 mM ammonium acetate solution (0.2 M, pH 8) of DFOB-L-LYS-DOTA(3) was mixed with 62 μL of a 50 mM aqueous solution of ZrCl4. The resulting 5:1 Zr(IV):DFOB-L-LYS-DOTA(3) solution was incubated at 37°C for 2 hours, and then... The mixture was stirred at room temperature for 20 hours. The product was analyzed by LC-MS. ESI-MS C 47 H 83 N 12 O 16 Zr + [M] + The calculated positive ion value for this value is m / z = 1161.51. See Figures 4b and 5b.

[0367] Example 4b: Formation of Lu(III)-DFOB-L-LYS-DOTA(Lu-3) 249 μL of a 2.5 mM ammonium acetate solution (0.2 M, pH 8) of DFOB-L-LYS-DOTA(3) was mixed with 62 μL of a 50 mM aqueous solution of LuCl3. The resulting 5:1 Lu(III):DFOB-L-LYS-DOTA(3) solution was stirred at 37°C for 2 hours, and then at room temperature for 20 hours. The product was analyzed by LC-MS. ESI-MSC 47 H 83 N 12 O 16 Positive ions calculated for Lu[M]:[M+H]+ 1247.55. See Figures 4c and 5c.

[0368] Example 5 Synthesis of the 4-component system DFOB-PPH-L-LYS-DOTA(4) The synthesis of the embodiment of DFOB-PPH-L-LYS-DOTA(4) is described in detail below. [ka]

[0369] PPH(NO t Bu)-Fmoc-L-LYS-(DOTA(O t Bu)3)-OH (4a) Fmoc-L-Lys(DOTA(O t A sample of Bu)3)-OH(1c)(L-LYS-DOTA,CAS:479081-06-6) (102.3 mg, 110.9 μmol) was dissolved in dimethylformamide (DMF) (2 mL), and then N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) (49.3 mg, 130 μmol) was added. This solution was stirred at room temperature for 10 minutes, and then diisopropylethylamine (DIPEA) (38.6 μL, 221.6 μmol) was added. This solution was stirred at room temperature for 30 minutes. 5-((5-aminopentyl)(tert-butoxy)amino)-5-oxopentanoic acid PPH(NO) was prepared by treating 5-(tert-butoxycarbonyl)amino)pentyl)amino)-5-oxopentanoic acid (CAS:2334242-42-9) with TFA (1:9). tA sample of Bu) (39.3 mg, 136.4 μmol) was added to this solution, and the solution was stirred at room temperature for 20 hours. A certain volume of DCM (20 mL) was added to the reaction mixture, and the mixture was extracted three times with 10 mL aliquots of saturated sodium bicarbonate. The organic layer containing the product was dried over anhydrous sodium sulfate, and after vacuum filtration, the solvent was removed under vacuum to obtain the residue, which was dissolved in DCM and semi-purified using automated flash chromatography (Grace Reverleris X2, 30 mL / min, 12 g cartridge, 0-0.4 min: 5:95 DCM:MeOH, 0.4-7.7 min: 5-28% DCM, 7.3-12.68 min: 28% DCM, 12.68-13.41 min: 28-100% DCM, 13.41-15.60 min: 100% DCM). The solvent was removed from the collected fraction under vacuum to obtain semi-purified PPH (NO). t Bu)-Fmoc-L-LYS-(DOTA(O t Bu)3)-OH(4a) was obtained.

[0370] DFOB-PPH(NO t Bu)-Fmoc-L-LYS-(DOTA(O t Bu)3)-OH(4b) PPH(NO t Bu)-Fmoc-L-LYS-(DOTA(O tA sample of Bu)3)-OH(4a) (167.4 mg, 140.3 μmol) was dissolved in dimethylformamide (DMF) (2 mL), and then N,N,N′,N′-tetramethyl-O-(1H-benzotriazole-1-yl)uronium hexafluorophosphate (HBTU) (69.5 mg, 183.3 μmol) was added. This solution was stirred at room temperature for 10 minutes, and then diisopropylethylamine (DIPEA) (49 μL, 281.3 μmol) was added. This solution was stirred at room temperature for 30 minutes, and then desferrioxamine B mesylate (1a) (117.8 mg, 179.4 μmol) was added, and the solution was stirred at room temperature for 24 hours. A certain volume of DCM (20 mL) was added to the reaction mixture, and the mixture was extracted three times with 10 mL aliquots of saturated sodium bicarbonate. The organic layer containing the product was dried over anhydrous sodium sulfate, vacuum filtered, and the solvent was removed under vacuum to obtain the reaction conditions DFOB-PPH(NO t Bu)-Fmoc-L-LYS-(DOTA(O t We obtained a product in which Fmoc of Bu)3)-OH(4b) was found to be a deprotected analog.

[0371] DFOB-PPH-L-LYS-DOTA(4) DFOB-PPH(NO t Bu)-Fmoc-L-LYS-(DOTA(O t Samples of a deprotected Fmoc analog of Bu)3)-OH(4b) (34.9 mg, 23.1 mg) were dissolved in TFA:DCM (9:1,450 μL:50 μL) with stirring at room temperature for 24 hours. The solvent was removed under vacuum, and the remaining TFA was removed by sequential treatment (dissolution / vacuum removal) with methanol and then toluene. The oily residue was suspended in 200 μL of water, and the pH of the solution was adjusted to 7 with aliquots of 1 M NaOH or HCl. The solvent was removed under vacuum, and DFOB-PPH-L-LYS-DOTA(4) was given as a pale yellow solid. See Figure 6.

[0372] Metal complex formation of DFOB-PPH-L-LYS-DOTA(4) Based on the results observed with DFOB-L-LYS-DOTA(3) and DFOB-DOTA(2), the inventors predicted that DFOB-PPH-L-LYS-DOTA(4) would selectively load metal ions such as Zr(IV) and Lu(III) (see Examples 2 and 4).

[0373] Example 6 89 Synthesis of compounds containing various moieties that enhance Zr bonding The inventors, PPH- N O, PPH- C S and PPH- N O C Monomers such as S may also be used to replace the four-component PPH system using the synthesis route described in Example 5. C O, PPH- N O C Monomers such as O may be used to replace PPH in a synthetic route that is a modification of the synthetic route described in Example 5 and further includes a reductive deprotection step in addition to steps (iii) and (iv). C O, PPH- N O C In the case of O, protection such as NO-Bn adducts is required. Methods for installing and removing protective groups are well known in the art.

[0374] Based on the results observed with DFOB-L-LYS-DOTA(3) and DFOB-DOTA(2), the inventors further predict that alternative four-component systems, such as compounds 4a-c shown below, will selectively load metal ions such as Zr(IV) and Lu(III) (see Examples 2 and 4). [ka]

[0375] Example 7 Synthesis of systems containing reverse hydroxyamic acid In the system described in detail in Example 6, 89 A chelate ligand selective for Zr89 We focused on "positive" hydroxamic acid monomers as a component to increase Zr affinity. An alternative system is: 8 9 A chelate ligand selective for Zr 89 Inverse hydroxamic acid is sometimes used as a component to enhance Zr affinity. Inverse hydroxamic acid is also known in the art as retrohydroxamic acid. Methods for preparing reverse hydroxamic acid are known in the art (see, for example, Lifa et al. (2015) Inorg. Chem. 54, 3573-3583, Tieu et al. (2017) Inorg. Chem. 56, 3719-3728 and Sresutharsan et al. (2017) J. Inorg. Biochem. 177, 344-351). Reverse hydroxamic acid may also be incorporated into the compounds of the present invention under the same or similar conditions as described in Examples 5 and 6. The structures of the positive hydroxamic acid 5-((5-aminopentyl)(hydroxy)amino)-5-oxopentanoic acid (PPH) and the corresponding system DFOB-PPH-L-LYS-DOTA(4) are shown in Figure 7, along with the corresponding inverse hydroxamic acid 4-(6-amino-N-hydroxyhexaneamide)butanoic acid (retro-PPH) and the related four-component system DFOB-retro-PPH-L-LYS-DOTA(retro-4).

[0376] Example 8 Synthesis of DFOB-PPH-DOTA DFOB-PPH-DOTA may be prepared using methods known in the art, for example, following a similar route to that described above for DFOB-PPH-L-LYS-DOTA(4) in Example 5. Therefore, DFOB-PHB-DOTA may be prepared according to the following diagram. [ka]

[0377] Example 9 Synthesis of DFOB-L-LYS(NCS)-DOTA [ka] A sample of DFOB-L-LYS-DOTA (5 mg, 4.65 μmol) was dissolved in a solution of isopropanol:water (3.8:1,316 μL:104 μL), and then p-phenylene-diisothiocyanate (9.2 mg, 47.9 μmol) in chloroform (500 μL) and triethylamine (8.28 μL, 46.5 μmol) was added. This solution was stirred at room temperature for 21.5 hours. After removing the chloroform under vacuum, the remaining solution was centrifuged to separate the supernatant. The supernatant was removed under vacuum to obtain a semi-purified product as a white powder. See Figure 8.

[0378] The inventors predicted that this compound would be suitable for conjugation to target sites such as antibodies. Furthermore, based on the results observed with DFOB-L-LYS-DOTA(3) and DFOB-DOTA(2), the inventors predicted that this compound would selectively load metal ions such as Zr(IV) and Lu(III) to the target site, whether or not it would form a conjugate. (See Examples 2 and 4).

[0379] Example 10 The compound (DFOB-L-LYS-EPS-PEG4-DOTA) was prepared as detailed below. The inventors further anticipate that the free amine group of the PEG group of the present invention is suitable for further chemistry that enables conjugate formation with the target moiety.

[0380] Synthesis of N-Boc-Amino-Acid-PEG4 Amino-Acid-PEG4 (121.5 mg, 0.46 mmol) and sodium hydroxide (23.4 mg, 0.59 mmol) were dissolved in a mixture of dioxane and water (2:1, 866:434 μL). After cooling this solution to 0°C, Boc2O (166.1 mg, 0.76 mmol) was added dropwise to a mixture of dioxane and water (2:1, 176.9:88.6 μL). This solution was stirred at room temperature for 21 hours. Upon completion, the solvent was removed under vacuum, and the residue was dissolved in water (20 mL). The residue was washed with ethyl acetate (3 x 12 mL), and the aqueous phase was adjusted to pH 1-2 with 1 M HCl, and further extracted with ethyl acetate (3 x 20 mL). The organic fractions were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under vacuum to obtain N-Boc-Amino-Acid-PEG4 as a colorless oily substance.

[0381] Synthesis of DFOB-L-LYS-EPS-N-Boc-PEG4-DOTA(OtBu)3 N-Boc-Amino-Acid-PEG4 (approximately 14.9 mg, 0.041 mmol) was dissolved in DMF (1 mL), then DIPEA (10.4 μL, 0.060 mmol) was added, and the reaction was stirred at room temperature for 10 minutes. HBTU (15.4 mg, 0.041 mmol) was added to this solution, and the solution was stirred at room temperature for 30 minutes. DFOB-L-LYS-EPS-DOTA(OtBu)3 (approximately 44.5 mg, 0.036 mmol) from DMF (5 mL) was added, and the solution was stirred at room temperature for 2 hours. Upon completion, the reaction solution was diluted with DCM (50 mL) and extracted with saturated sodium bicarbonate (3 x 25 mL) and brine (1 x 25 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under vacuum to obtain DFOB-L-LYS-EPS-N-Boc-PEG4-DOTA(OtBu)3 as a yellow oily substance (28.5 mg, 46.9%).

[0382] Synthesis of DFOB-L-LYS-EPS-PEG4-DOTA DFOB-L-LYS-EPS-N-Boc-PEG4-DOTA(OtBu)3 (28.5 mg, 0.019 mmol) was dissolved in a TFA:DCM (9:1, 2 mL) solution and stirred at room temperature for 18 hours. Upon completion, the solvent was removed under vacuum. The residue was dissolved in methanol (5 mL), the solvent was removed under vacuum, and the process was repeated with toluene (5 mL). The residue was neutralized to pH 7 with 1 M NaOH and 1 M HCl to give DFOB-L-LYS-EPS-PEG4-DOTA as a pale yellow solid. [ka]

[0383] Example 11 The compound (NCS-activated-DFOB-L-LYS-EPS-PEG4-DOTA-compound D2) was prepared as detailed below. [ka]

[0384] Synthesis of L-Fmoc-LYS-EPS-DOTA(OtBu)3 DIPEA (3.6 mL, 20.67 mmol) was added to a DMF solution (50 mL) of DOTA(OtBu)3 (1.7677 g, 3.09 mmol). The mixture was stirred at room temperature for 10 minutes. Then HBTU (1.1728 g, 3.09 mmol) was added, and the mixture was stirred at room temperature for a further 30 minutes. Next, Fmoc-Lys-OH HCl (1.2643 g, 3.43 mmol) was added, and the resulting mixture was stirred at room temperature for a further 2 hours. Upon completion, the solvent was removed under vacuum. The residue was purified by solid-phase extraction (Method A). The collected fractions were combined and freeze-dried to obtain L-Fmoc-Lys-DOTA(OtBu)3(1) as a yellow / white solid (1.7402 g, 1.63 mmol, 52.8%).

[0385] Synthesis of DFOB-L-Fmoc-LYS-EPS-DOTA(OtBu)3 DIPEA (194 μL, 1.11 mmol) was added to a DMF solution (50 mL) of L-Fmoc-LYS-EPS-DOTA(OtBu)3 (595.3 mg, 0.65 mmol). The mixture was stirred at room temperature for 10 minutes. HBTU (258.2 mg, 1.10 mmol) was then added, and the resulting mixture was stirred at room temperature for a further 30 minutes. Next, desferrioxamine B mesylate (444.1 mg, 0.67 mmol) was added, and the resulting mixture was stirred at 50°C for a further 1 hour. Upon completion, the reaction solution was removed under vacuum. The resulting residue was diluted with DCM (500 mL) and extracted with saturated sodium bicarbonate (3 x 250 mL) and saturated brine (1 x 250 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under vacuum to give DFOB-L-Fmoc-Lys-EPS-DOTA(OtBu)3 as a yellow / green oily substance (698 mg, 0.48 mmol, 70.6%).

[0386] Synthesis of DFOB-L-LYS-EPS-DOTA(OtBu)3 DFOB-L-Fmoc-Lys-EPS-DOTA(OtBu)3 (698 mg, 0.48 mmol) was dissolved in piperidine:DMF (1:4) (1 mL:4 mL) solution and stirred at room temperature for 1 hour. Upon completion, the solvent was removed under vacuum. Diethyl ether was then added to the resulting residue and stirred for 10 minutes, after which the ether was decanted. The solvent was removed under vacuum to obtain DFOB-L-Lys-DOTA(OtBu)3 as a yellow / white crystalline product (539.4 mg, 0.43 mmol, 90%).

[0387] Synthesis of N-Boc-Amino-Acid-PEG4 Amino-Acid-PEG4 (395.3 mg, 1.49 mmol) and sodium hydroxide (84.7 mg, 2.12 mmol) were dissolved in a mixture of dioxane and water (2:1, 4 mL). After cooling the solution to 0°C, Boc2O (613.9 mg, 2.81 mmol) in a mixture of dioxane and water (2:1, 1 mL) was added dropwise. The solution was stirred at room temperature for 18 hours. Upon completion, the solvent was removed under vacuum, and the residue was dissolved in (20 mL). The residue was washed with ethyl acetate (3 x 12 mL), the aqueous phase was adjusted to pH 1-2 with 1 M HCl, and further extracted with ethyl acetate (3 x 20 mL). The organic fractions were combined, dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under vacuum to obtain N-Boc-Amino-Acid-PEG4 as a pale yellow oily substance (387.5 mg, 1.06 mmol, 71.1%).

[0388] Synthesis of DFOB-L-LYS-EPS-N-Boc-PEG4-DOTA(OtBu)3 N-Boc-Amino-Acid-PEG4 (118.8 mg, 0.33 mmol) was dissolved in DMF (50 mL), then DIPEA (113.4 μL, 0.65 mmol) was added, and the reaction was stirred at room temperature for 10 minutes. HBTU (149.5 mg, 0.64 mmol) was added to this solution, and it was stirred at room temperature for 30 minutes. DFOB-L-LYS-EPS-DOTA(OtBu)3 (539.4 mg, 0.43 mmol) was added, and the solution was stirred at room temperature for approximately 18.5 hours. Upon completion, the reaction solution was removed under vacuum. The resulting residue was diluted with DCM (100 mL) and extracted with saturated sodium bicarbonate (3 x 50 mL) and saturated brine (1 x 50 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under vacuum to give DFOB-L-LYS-EPS-N-Boc-PEG4-DOTA(OtBu)3 as a yellow oily substance (465 mg, 0.29 mmol, 87.9%).

[0389] Synthesis of DFOB-L-LYS-EPS-PEG4-DOTA DFOB-L-LYS-EPS-N-Boc-PEG4-DOTA(OtBu)3 (465 mg, 0.29 mmol) was dissolved in a TFA:DCM (9:1, 5 mL) solution and stirred at room temperature for approximately 19 hours. Upon completion, the solvent was removed under vacuum. The residue was dissolved in toluene (10 mL), rinsed with a minimum amount of methanol, transferred from the vial, and then the solvent was removed under vacuum. The residue was removed. The resulting residue was purified by SPE (Method B) to obtain DFOB-L-LYS-EPS-PEG4-DOTA as a yellow oily substance (115.7 mg, 0.09 mmol, 31.0%).

[0390] Synthesis of NCS-activated-L-LYS-EPS-PEG4-DOTA In this synthesis step, two reactions were carried out in parallel. DFOB-L-LYS-EPS-PEG4-DOTA (13.2 mg, 10.2 mg, total 0.018 mmol) was dissolved in DMF (1 mL, 1 mL) in Eppendorf tubes, and triethylamine (28 μL, 22 μL, total 0.29 mmol) was added to this solution. In a separate Eppendorf tube, a DMF solution of 1,4-phenylenediisothiocyanate (22.3 mg, 17.7 mg, total 0.250 mmol) was prepared (920 μL, 484 μL). The DFOB-L-LYS-EPS-PEG4-DOTA solution was added to the 1,4-phenylenediisothiocyanate solution in five aliquots (5 x 206 μL, 5 x 204 μL), with pulses between additions. Each reaction was divided into additional Eppendorf tubes (total of 4 tubes). The resulting mixture was centrifuged at 800 rpm for 1.5 hours. Upon completion, the resulting solution was divided into five additional Eppendorf tubes (162 μL and 126 μL per tube, 24 tubes in total), diethyl ether (approximately 508 μL and 392 μL respectively) was added, and the resulting solution was stored in the refrigerator for 2 hours. The resulting solution was then centrifuged at 12000 rpm for 3 minutes, and the ether was decanted. The pellets were washed with cold diethyl ether (approximately 564 μL and 436 μL respectively) and air-dried. The pellets were dissolved in DMF (approximately 22.5 μL and 17.4 μL respectively) and MeOH (approximately 169 μL and 131 μL respectively), then diethyl ether (approximately 508 μL and 392 μL respectively) was added, and the mixture was refrigerated for a further 23 hours. Upon completion, the resulting solution was centrifuged at 12000 rpm for 3 minutes, and the ether was decanted. The pellets were further washed with cold diethyl ether (approximately 564 μL and 436 μL respectively) and air-dried. The pellets were then transferred to a vial containing methanol and dried under vacuum to obtain crude NCS-activated-DFOB-L-LYS-EPS-PEG4-DOTA (compound D2) as a yellow / white oily substance. The crude substance was purified by HPLC, and the collected fraction was freeze-dried to obtain pure compound D2 as a white solid (2.9 mg, 0.002 mmol, 11.1%). This compound was characterized using LC-MS (Figures 13-16), and based on this method, its purity was >95% (Figure 13).

[0391] High-performance liquid chromatography Preparative high-performance liquid chromatography (HPLC) was performed using a Shimadzu LC-20 series LC system equipped with two LC-20AP pumps, a SIL-10AP autosampler, an SPD-20AUV / VIS detector, and an FRC-10A fraction collector. For semi-preparative purification, a flow rate of 20 mL min was used. -1 Shimadzu Shimpack GIS column (inner diameter 150 x 10 mm, 5 mL min) -1 A 5 μm particle size was used. The organic phase (B) consisted of ACN:TFA (99.95:0.05). The aqueous phase (A) consisted of H2O:TFA (99.95:0.05). Spectral data was acquired and processed using Shimadzu LabSolutions Software (version 5.98). In this method, a flow rate of 5 mL min was used. -1 A gradient was used, consisting of 5 minutes in 20-25% solvent B, 35 minutes in 25-45% solvent B, and 5 minutes in 20% solvent B.

[0392] solid phase extraction Solid-phase extraction (SPE) was performed using Waters SEP-PAK C18 5g and 2g vacuum cartridges on a manual vacuum manifold.

[0393] Method A The cartridge was conditioned with one column volume of CAN, then one column volume of Milli-Q water. The sample was loaded into 100% Milli-Q water, and all remaining water was removed from the reaction vessel. The residue was rinsed with a minimum amount of CAN. Then the cartridge was washed with one column volume of Milli-Q water. The cartridge was then subjected to 20-55% CAN in two column volumes of Milli-Q water, and the 45-55% fraction was collected.

[0394] Method B The cartridge was conditioned with one column volume of CAN, and then with one column volume of Milli-Q water. The sample was loaded into 100% Milli-Q water. The cartridge was then washed with one column volume of Milli-Q water. The cartridge was then subjected to four columns volume of Milli-Q water with 80% CAN, and these fractions were collected.

[0395] Example 12 Formation of a conjugate of NCS-activated DFOB-L-LYS-EPS-PEG4-DOTA (compound D2 or D2) to Girentuximab 1 mg of NCS-activated DFOB-L-LYS-EPS-PEG4-DOTA (compound D2 or D2) (~20-fold molar excess) dissolved in dimethyl sulfoxide (DMSO, 2.5 mg / mL) was added to 6 mg of Girentuximab in 1x phosphate-buffered saline (PBS, 10 mg / mL). 6% v / v 1 MNa2CO3 was added to this mixture at a final reaction pH of 8.5-9.0. The reaction mixture was allowed to react at 37°C for 1 hour with gentle stirring at 550 rpm. The resulting mixture was purified 8-10 times using AmiconSpin Membranes (10 kDa MWCO, 0.5 mL). The purity of the conjugated compounds was analyzed by HPLC (UV detection at 280 nm), and the chelator-to-antibody ratio was determined to be 1-2 for each antibody in this study by matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI TOF-MS).

[0396] Example 13 Radiolabeling of compound D2-mAb Compound D2-mAb (in this case, mAb = Girentuximab) in a buffer at an excess antibody concentration. 89 Zr was incubated at 37°C for 60 minutes with stirring at 550 rpm. Radioactive radioTLC was used to extract unbound samples. 89The absence of Zr was confirmed. The compound was rotated using a ZebaSpin desalting column (40kDaMWCO, 2mL), and the radiochemical yield of the substance was determined to be >95%. The substance was then injected into a mouse HT-29 xenograft model for positron emission tomography (PET) contrast imaging. DFOB-mAb[ 89 The Zr control gives a quantitative radiochemical yield. Compound D2-mAb is used in excess antibody concentration. 177 Lu and DOTA-mAb [ incubated at 37°C for 60 minutes while stirring at 400 rpm] 177 The Lu control provides quantitative radiochemical yields.

[0397] Example 14 Each control compound DFOB-mAb[ 89 Zr] and DOTA-mAb[ 177 Compared with Lu, compound D2-mAb[ 89 Zr] and compound D2-mAb[ 177 In vitro trial of Lu Cell binding assay Sowing and incubation HT-29 cells were placed in a 24-well plate at a concentration of 7.5 x 10⁶ 2 Seed cells / well, with a final count of approximately 2.5 x 10⁶ cells per well. 5 Cells were formed. Radiolabeled mAbs (compound D2-mAb[ 89 Zr], Compound D2-mAb[ 177 Lu], DFOB-mAb[ 89 Zr], DOTA-mAb[ 177 Lu) was diluted in serum-free (SF) cell growth medium (0.02 μg, 15 mCi), and 100 μL of each solution was added to each well. The cells were incubated in a humidified incubator under a 5% CO2 atmosphere at 37°C for three different durations: 0.5, 1, and 2 hours.

[0398] Determination of membrane-bound fraction At each time point, the growth medium was removed, and the cells were washed twice with ice-cold PBS (1x, pH 7.4, 200 μL) to stop internal migration. The receptor-binding radiolabeled mAb was then removed using ice-cold glycine buffer containing 4M urea (0.2M, pH 2.0, 200 μL) for 5 minutes. The buffer was collected from each well, and the radioactivity was measured with a gamma counter to determine the membrane-bound fraction. The cells were then washed once with the same glycine buffer.

[0399] Determination of internally migrated fractions The cells were treated with sodium hydroxide (1N, 200 μL) for 30 minutes, rinsed, and the fraction that had migrated into the cells was collected. The radioactivity of the collected fraction was then measured using a gamma counter.

[0400] non-specific binding After the assay, the cells in four non-experimental wells were counted, and the average cell count was used to estimate the number of cells per well. Cells in each well were co-incubated with non-radioactively labeled cells (2 μg, 50 μL) and radioactively labeled cells (0.02 μg, 50 μL), and nonspecific binding and internal migration were determined by repeating the above procedure for membrane-bound and internal migration fractions.

[0401] From these data, compound D2-mAb[ 177 Lu] and DOTA-mAb[ 177 The fractions of film-bound or internally migrated radiolabeled mAb in Lu were similar at 1 hour and 2 hours (Figures 17 and 18), and compound D2-mAb[ 89 Zr] and DFOB-mAb[ 89 The fractions of Zr-bound or internally migrated radiolabeled mAbs were similar at 1 hour and 2 hours (Figures 19 and 20).

[0402] Example 15 Each control compound DFOB-mAb[ 89 Zr] and DOTA-mAb[ 177 Compared with Lu, compound D2-mAb[ 89 Zr] and compound D2-mAb[ 177 In vivo and ex vivo trials of Lu] 8-week-old male Balb / c nude mice were given HT-29 (10x10) in 50 μL of 50:50 Matrigel. 6 Cells in phosphate-buffered saline were subcutaneously injected into the right flank of each mouse. Labeled mAbs (compound D2-mAb[ 89 Zr] or DFOB-mAb[ 89 Zr) was injected into the tail vein (29 Gneedle; ~1-4 MBq), and then the mice were... 89 Zr was imaged at various time points using a Siemens Inveon PET-CT scanner, the animals were euthanized after 48 hours, and the recovered organs were counted by gamma counting.

[0403] In vivo and ex vivo distribution within the body 89 Mice injected with Zr-labeled mAbs were imaged at 4, 24, and 48 hours post-injection (Figure 21), and their in vivo distribution was measured at 48 hours (Figure 22). Gamma counting was performed at 48 hours post-injection. 89 Zr and 177 Organs were collected from mice injected with Lu to quantify their organ distribution (Figure 23).

[0404] Example 16 Compound D2-mAb[ nat Lu simple 89 Zr] and compound D2-mAb[ 177 Lu simple nat Preparation of Zr As shown in the diagram below, compound D2 is compound D2[ nat It can be loaded into non-toxic natural Lu(III) to create compound D2[ nat Lu] then forms a compound with mAb, 89 Zr-labeled compound D2-mAb for immunoassay PET contrast imaging [ nat Lu simple 89 Compound D2-mAb[ for creating Zr] nat Create Lu. [ka]

[0405] Compound D2-mAb[ nat Lu simple 89 If it is Zr, it is prepared by incubating compound D2 with natural Lu(III) that binds to the DOTA region of compound D2. Compound D2[ nat If it is Lu, it forms a compound with mAb and compound D2-mAb[ nat We created Lu, and this compound is useful for immunological PET contrast imaging, D2-mAb[ nat Lu simple 89 Radially label with 89Zr to create [Zr].

[0406] Similarly, as shown in the diagram below, compound D2 is compound D2[ nat To create Zr, it can be loaded into non-toxic natural Zr(IV) and compound D2[ nat Zr then forms a compound with mAb, 177 The therapeutic compound D2-mAb[ 177 Lu simple nat D2-mAb[ to create Zr] nat Create [Zr]. [ka]

[0407] Compound D2-mAb[ 177 Lu simple nat If it is Zr, it is prepared by incubating compound D2 with natural Zr(IV) that binds to the DFOB region of compound D2. nat If it is Zr, it forms a compound with mAb and compound D2-mAb[ nat We created Zr, and if this compound is useful for treatment, then it is the compound D2-mAb[ 177 Lu simple nat Radiation labeling with 177 Lu to create [Zr]

[0408] Compound D2-mAb[ nat Lu simple 89 Zr] and compound D2-mAb[ 177 Lu simple natZr(IV) exhibits identical pharmacokinetic and intracellular distribution characteristics, making it useful for search methods. This method utilizes natural Lu(III) and natural Zr(IV), both of which are non-toxic metal ions.

Claims

1. It is a compound, ８９ A first chelate ligand selective for Zr, and ８９ It contains a second chelate ligand that is selective for radionuclides other than Zr that have potential as pharmaceuticals, The first and second chelate ligands are covalently bonded by a linker group, The linker group comprises one or more amino acid residues. The first chelate ligand is 【Chemistry 1】 And, R １ teeth, 【Chemistry 2】 And, Y is CH ２ , O or S, X is CH ２ , O or S, Each Z is CH ２ and are selected independently of O, n is either 0 or 1, and m is either 0 or 1, or The first chelate ligand is 【Transformation 3】 and 【Chemistry 4】 Selected from the group consisting of, The second chelate ligand is 【Transformation 5】 and 【Transformation 6】 Selected from the group consisting of, compound.

2. The second chelating ligand is ９０ Y, １５３ Sm, １６１ Tb, １７７ Lu, ２１３ Bi and ２２５ Ac or a combination thereof, the compound according to claim 1.

3. The aforementioned ８９ The first chelate ligand selective for Zr is, ９０ The compound according to claim 1 or 2, which is also selective for Nb.

4. The aforementioned compound is of formula (I) 【Transformation 7】 It is a compound of, A is the first chelate ligand, B is the second chelate ligand, L is a linker group. The compound according to any one of claims 1 to 3.

5. The first chelate ligand is a compound according to any one of claims 1 to 4, comprising a hydroxamic acid group.

6. The compound according to any one of claims 1 to 5, wherein the first chelate ligand is a hexadentate chelate ligand.

7. The compound according to any one of claims 1 to 5, wherein the first chelate ligand is an octate chelate ligand.

8. Formula (II) 【Transformation 8】 A compound of, Ch １ It is the base of desferrioxamine B, Ch ２ This is a group selected from the group consisting of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), α-(2-carboxyethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTAGA), or 7-[2-[bis(carboxymethyl)amino]ethyl]hexahydro-1H-1,4,7-triazonine-1,4(5H)-diacetic acid (NETA), and L is a linker group, The linker group comprises one or more amino acid residues. compound.

9. The linker group comprises the shortest linear chain of up to 30 atoms, according to any one of claims 1 to 8.

10. The linker group is an optionally substituted C, optionally sandwiched between one or more groups selected from a heteroatom, alkene, alkyne, cycloalkyl, heterocyclyl, amide, ester, ketone, target moiety, or a group capable of forming a stable bond with the target moiety, and combinations thereof. １－２０ The compound according to claim 9, wherein it is an alkyl group.

11. The compound according to any one of claims 1 to 9, wherein the linker group comprises L-lysine, L-glutamic acid, L-aspartic acid, or a combination thereof.

12. The compound according to claim 9, wherein the linker group is substituted with a target moiety or a substituent capable of bonding to the target moiety.

13. The compound according to claim 12, wherein the target portion is girentuximab.

14. A compound according to any one of claims 1 to 13, and a complex comprising one potentially pharmaceutically active nuclide or two different potentially pharmaceutically active nuclides.

15. The complex according to claim 14, comprising a compound according to any one of claims 1 to 13 and a nuclide with potential as a pharmaceutical.

16. A compound according to any one of claims 1 to 13 or a complex according to claim 14 or 15, and A composition containing pharmaceutically acceptable excipients.

17. A method for producing the compound according to any one of claims 1 to 13, comprising binding the first chelate ligand to the second chelate ligand.

18. A composition for the treatment of neoplastic diseases, comprising the complex of claim 14 or 15.

19. A composition comprising the complex of claim 14 or 15 for the diagnosis and / or prognosis diagnosis of a target disease or condition by imaging.

20. The composition according to claim 19, wherein the imaging method includes the step of contacting the compound according to any one of claims 1 to 13 or the composition according to claim 16 with one or two radionuclides of therapeutic or diagnostic potential to form the complex according to claim 14 or 15.

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