Macrocyclic complexes of radionuclides and their use in radiotherapy of cancer

Abstract

The present technology provides compounds and compositions comprising such compounds useful for targeted radiation therapy of cancer and / or mammalian tissues that overexpress prostate-specific membrane antigen ("PSMA"), the compounds having the following formula (I): (IA), or a pharmaceutically acceptable salt thereof (II), or a pharmaceutically acceptable salt thereof, wherein M 1 is, independently at each occurrence, an alpha-emitting radionuclide. Corresponding compounds of such compounds are also disclosed.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit and priority of U.S. Provisional Application No. 62 / 769,989, filed Nov. 20, 2018; U.S. Provisional Application No. 62 / 788,700, filed Jan. 4, 2019; and U.S. Provisional Application No. 62 / 792,835, filed Jan. 15, 2019, each of which is hereby incorporated by reference in its entirety for any and all purposes.

[0002] Rights in U.S. Government Licenses This invention was made with government support under grant number UL1TR00457 awarded by the National Institutes of Health. The U.S. government has certain rights in this invention.

Background Art

[0003] This technology generally relates to macrocyclic complexes of alpha - emitting radionuclides, as well as compositions and methods of use that include such compounds.

Summary of the Invention

[0004] In one aspect, a compound of formula I is

[0005]

Chemical Formula

[0006] In related embodiments, the compound of formula IA is

[0007] [Chemical formula] [wherein M 1 is an alpha-emitting radionuclide; Z 1 is H or -X 1 -W 2 and Z 2 is OH or NH-W 3 and Z 3 is H or W 7 and alpha is 0 or 1; X 1 is O, NH, or S; W 2 and W 3 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2) w-R’ (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH2CH2-(OCH2CH2) x -OR’ (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2) y -R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH2CH2-(OCH2CH2) z -OR’ (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or one or more of epoxy groups; W 5 and W 7 are each independently OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2) w -R’ (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH2CH2-(OCH2CH2) x -OR’ (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y x -R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH2CH2-(OCH2CH2) z-OR’ (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or may be substituted with one or more of an epoxide group; R’ is, each occurrence independently, H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C 10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl] or a pharmaceutically acceptable salt thereof is provided.

[0008] In a further related aspect, the technology provides a compound (a "targeting compound") useful for targeted radiotherapy of cancer and / or mammalian tissues that overexpress prostate-specific membrane antigen ("PSMA"), the compound having the formula II

[0009] [Chemical formula] [wherein M 1 is an alpha-emitting radionuclide; Z 1 is H or -L 3 -R 22 and Z 2 is OH or NH-L 4 -R 24 and Z 3 is H or -L 6 -R 28 and α is 0 or 1; X 1 is O, NH, or S; L 3 L 4 L5 or L 6 is, for each occurrence, independently, a linking or linker group; R 22 R 24 R 26 and R 28 are each independently an antibody, an antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, a binding polypeptide (e.g., a selective target-directed oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase-containing moiety (e.g., an oligonucleotide, a DNA or RNA vector, or an aptamer), or a lectin] or a pharmaceutically acceptable salt thereof.

[0010] In a further related aspect, a modified antibody, a modified antibody fragment, or a modified binding peptide is provided that comprises a bond resulting from the conjugation of a compound of formula I or a pharmaceutically acceptable salt thereof to an antibody, an antibody fragment, or a binding peptide. In related aspects, the modified antibody, the modified antibody fragment, or the modified binding peptide comprises a bond resulting from the conjugation of a compound of formula IA or a pharmaceutically acceptable salt thereof to an antibody, an antibody fragment, or a binding peptide.

[0011] In any embodiment and / or aspect disclosed herein (for simplicity, hereinafter referred to as "in any embodiment disclosed herein"), the antibody may include pembrolizumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, siltuximab, semipramosumab, nivolumab, pembrolizumab, orlatumumab, atezolizumab, abevizumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, cixutumumab, glembatumumab, nimotuzumab, catumaxomab, or etaracizumab. In any embodiment disclosed herein, the antibody fragment may include an antigen-binding fragment of pembrolizumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, siltuximab, semipramosumab, nivolumab, pembrolizumab, orlatumumab, atezolizumab, abevizumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, cixutumumab, glembatumumab, nimotuzumab, catumaxomab, or etaracizumab. In any embodiment disclosed herein, the binding peptide may include a prostate-specific membrane antigen ("PSMA") binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a separase binding compound, or a binding fragment thereof.

[0012] In another aspect, the present technology also provides a composition (e.g., a pharmaceutical composition) and a medicament comprising any one of the embodiments of a compound of formula I, IA or II (or a pharmaceutically acceptable salt thereof) disclosed herein, and a pharmaceutically acceptable carrier or one or more additives or fillers. In a similar aspect, the present technology also provides a composition (e.g., a pharmaceutical composition) and a medicament comprising any one of the embodiments of a modified antibody, modified antibody fragment, or modified binding peptide of the present technology disclosed herein, and a pharmaceutically acceptable carrier or one or more additives or fillers.

[0013] In one aspect, there is provided a method of treating a subject, the method comprising administering to the subject a targeting compound of the present technology, or administering to the subject a modified antibody, modified antibody fragment, or modified binding peptide of the present technology. In any of the embodiments disclosed herein, the subject may have a problem of cancer and / or mammalian tissue overexpressing prostate specific membrane antigen ("PSMA").

[0014] In one aspect, there is provided a compound comprising a first domain having a blood protein binding moiety with low specific affinity for blood proteins, a second domain having a tumor targeting moiety with high affinity for tumor antigens, and a third domain having a chelator. BRIEF DESCRIPTION OF THE DRAWINGS

[0015]

Figure 1-1

Figure 1-2

Figure 2-1

Figure 2-2

Figure 3-1

Figure 3-2

Mode for Carrying Out the Invention

[0016] The following terms are used throughout as defined below.

[0017] As used herein and in the appended claims, singular articles such as "a", "an", and "the" and similar referents related to the recitation of these elements (in particular, related to the following claims) shall be construed to include the singular and plural unless otherwise indicated herein or clearly contradicted by the context. The detailed description of a range of values herein is merely intended to serve as an abbreviated way of referring individually to each separate value falling within that range, and each separate value is incorporated herein as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by the context in another way. The use of any and all examples or exemplary language (e.g., "such as") provided herein is merely intended to better clarify the embodiments and does not result in a limitation in the claims unless otherwise stated. The language herein should not be understood as indicating any non-claimed elements as essential.

[0018] As used herein, "about" is understood by one of ordinary skill in the art and varies to some extent depending on the context in which it is used. In the event of the use of a term that is not obvious to one of ordinary skill in the art, given the context in which it is used, "about" means plus or minus 10% of a particular term; for example, "about 10 wt%" is understood to mean "9 wt% to 11 wt%". When "about" precedes a term, it should be understood that the term is to be interpreted as disclosing the "about" term as well as the term not modified by "about"; for example, "about 10 wt%" discloses "9 wt% to 11 wt%" and also discloses "10 wt%".

[0019] Generally, reference to some elements, such as hydrogen or H, is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, the R group also includes deuterium and tritium. Thus, compounds containing radioactive isotopes such as tritium, C 14 , P 32 and S 35 etc. are within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to one of ordinary skill in the art based on the disclosure herein.

[0020] Generally, "substituted" means an organic group (e.g., an alkyl group) as defined below, in which one or more bonds to hydrogen atoms contained therein are replaced by single bonds to non-hydrogen or non-carbon atoms. Substituents also include groups in which one or more bonds to carbon(s) or hydrogen(s) atoms are replaced by one or more bonds, including double or triple bonds to heteroatoms. Thus, a substituent is substituted with one or more substituents unless otherwise specified. In some embodiments, a substituent is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituents include halogen (i.e., F, Cl, Br, and I); hydroxyl; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyl (oxo); carboxylate; ester; urethane; oxime; hydroxylamine; alkoxyamine; aralkoxyamine; thiol; sulfide; sulfoxide; sulfone; sulfonyl; pentafluorosulfanyl (i.e., SF5), sulfonamide; amine; N-oxide; hydrazine; hydrazide; hydrazone; azide; amide; urea; amidine; guanidine; enamine; imide; isocyanate; isothiocyanate; cyanate; thiocyanate; imine; nitro group; nitrile (i.e., CN); and the like.

[0021] Substituted ring groups, such as substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl groups, also include rings and ring systems in which a single bond to a hydrogen atom is replaced by a single bond to a carbon atom. Thus, substituted cycloalkyl, aryl, heterocyclyl, and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.

[0022] As used herein, C m ~C n For example, C1~C 12, C1 to C8, or C1 to C6, when used in front of a group, means a group containing from m to n carbon atoms.

[0023] Alkyl groups include straight-chain and branched-chain alkyl groups having from 1 to 12 carbon atoms, usually from 1 to 10 carbon atoms, or in some embodiments, from 1 to 8, from 1 to 6, or from 1 to 4 carbon atoms. Examples of straight-chain alkyl groups include, for example, groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. The alkyl group may or may not be substituted. Representative substituted alkyl groups may be substituted one or more times with substituents such as those described above, and include, but are not limited to, haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, etc.

[0024] The cycloalkyl group includes mono-, bi- or tricyclic alkyl groups having 3 to 12 carbon atoms in the ring(s), or in some embodiments, 3 to 10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms. Exemplary monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, and in other embodiments, the number of carbon atom rings ranges from 3 to 5, 3 to 6, or 3 to 7. Bicyclic and tricyclic ring systems include bridged cycloalkyl groups and fused rings, such as, but not limited to, bicyclo[2.1.1]hexane, adamantyl, decalinyl, etc. The cycloalkyl group may or may not be substituted. The substituted cycloalkyl group may be substituted one or more times with the non-hydrogen and non-carbon groups defined above. However, the substituted cycloalkyl group also includes rings substituted with the linear or branched alkyl groups defined above. Representative substituted cycloalkyl groups may be mono-substituted or more than mono-substituted, and can be, for example, but not limited to, 2,2-, 2,3-, 2,4-, 2,5- or 2,6-disubstituted cyclohexyl groups, etc., which may be substituted with substituents such as those described above.

[0025] A cycloalkylalkyl group is an alkyl group as defined above, wherein a hydrogen or carbon bond of the alkyl group is replaced by a single bond to a cycloalkyl group as defined above. In some embodiments, the cycloalkylalkyl group has from 4 to 16 carbon atoms, from 4 to 12 carbon atoms, and typically from 4 to 10 carbon atoms. The cycloalkylalkyl group may or may not be substituted. A substituted cycloalkylalkyl group may be substituted in the alkyl, cycloalkyl, or both the alkyl and cycloalkyl moieties of this group. Representative substituted cycloalkylalkyl groups may be mono-substituted or substituted more than once, and may be, for example, but not limited to, mono-, di-, or tri-substituted with substituents such as those described above.

[0026] Alkenyl groups include straight-chain and branched-chain alkyl groups as defined above, except that at least one double bond is present between two carbon atoms. Alkenyl groups have from 2 to 12 carbon atoms, typically from 2 to 10 carbon atoms, or in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkenyl group has one, two, or three carbon-carbon double bonds. Examples include, but are not limited to, among others, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2. Alkenyl groups may or may not be substituted. Representative substituted alkenyl groups may be mono-substituted or substituted more than once, and may be, for example, but not limited to, mono-, di-, or tri-substituted with substituents such as those described above.

[0027] The cycloalkenyl group includes the cycloalkyl group as defined above having at least one double bond between two carbon atoms. The cycloalkenyl group may or may not be substituted. In some embodiments, the cycloalkenyl group may have one, two or three double bonds, but does not include aromatic compounds. The cycloalkenyl group has from 4 to 14 carbon atoms, or in some embodiments, from 5 to 14 carbon atoms, from 5 to 10 carbon atoms, and further 5, 6, 7, or 8 carbon atoms. Examples of the cycloalkenyl group include cyclohexenyl, cyclopentenyl, cyclohexadienyl, cyclobutadienyl, and cyclopentadienyl.

[0028] The cycloalkenylalkyl group is the alkyl group as defined above in which a hydrogen or carbon bond of the alkyl group is replaced by a single bond to the cycloalkenyl group as defined above. The cycloalkenylalkyl group may or may not be substituted. The substituted cycloalkenylalkyl group may be substituted with alkyl, cycloalkenyl or alkyl and cycloalkenyl moieties of the group. Representative substituted cycloalkenylalkyl groups may be substituted one or more times with substituents such as those described above.

[0029] An alkynyl group includes the straight-chain and branched-chain alkyl groups defined above, except that at least one triple bond exists between two carbon atoms. An alkynyl group has from 2 to 12 carbon atoms, usually from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkynyl group has one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to, among others, -C≡CH, -C≡CCH3, -CH2C≡CCH3, -C≡CCH2CH(CH2CH3)2. The alkynyl group may or may not be substituted. Representative substituted alkynyl groups may be mono-substituted or substituted more than once, and may be mono-substituted, di-substituted, or tri-substituted, for example, but not limited to, by substituents such as those described above.

[0030] An aryl group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Aryl groups herein include monocyclic, bicyclic, and tricyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, the aryl group contains from 6 to 14 carbons in these ring moieties, and otherwise from 6 to 12, and further from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. The aryl group may or may not be substituted. The term "aryl group" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). Representative substituted aryl groups may be mono-substituted or substituted more than once. For example, mono-substituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, and may be substituted by substituents such as those described above.

[0031] An aralkyl group is an alkyl group as defined above, wherein a hydrogen or carbon bond of the alkyl group is replaced by a single bond to an aryl group as defined above. In some embodiments, the aralkyl group contains from 7 to 16 carbon atoms, from 7 to 14 carbon atoms, or from 7 to 10 carbon atoms. The aralkyl group may or may not be substituted. A substituted aralkyl group may be substituted in the alkyl and aryl moieties of the alkyl, aryl or groups thereof. Representative aralkyl groups include, but are not limited to, benzyl and phenethyl groups and fused (cycloalkylaryl) alkyl groups such as 4-indanylethyl. Representative substituted aralkyl groups may be substituted one or more times with substituents such as those described above.

[0032] Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non-aromatic ring compounds containing three or more ring members, one or more of which are heteroatoms, for example, but not limited to, N, O, and S. In some embodiments, the heterocyclyl group contains 1, 2, 3, or 4 heteroatoms. In some embodiments, the heterocyclyl group includes mono-, bi-, and tricyclic rings having from 3 to 16 ring members, and other such groups have from 3 to 6, from 3 to 10, from 3 to 12, or from 3 to 14 ring members. Heterocyclyl groups include aromatic, partially unsaturated, and saturated ring systems, for example, imidazolyl, imidazolinyl, and imidazolidinyl groups. The phrase "heterocyclyl group" includes those containing fused aromatic and non-aromatic groups, for example, fused ring species including benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. This phrase includes bridged polycyclic ring systems containing heteroatoms, for example, but not limited to, quinuclidinyl, etc. The heterocyclyl group may or may not be substituted.Heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidinyl, indolyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolidinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Representative substituted heterocyclic groups may be mono-substituted or multi-substituted more than once, and for example, but not limited thereto, may be 2-, 3-, 4-, 5-, or 6-substituted, or may be a pyridyl or morpholinyl group disubstituted with various substituents such as those described above.

[0033] A heteroaryl group is an aromatic ring compound containing 5 or more ring members, one or more of which are heteroatoms such as, but not limited thereto, N, O, and S. Heteroaryl groups include, but are not limited to, for example, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups include fused ring compounds where all rings are aromatic, such as the indolyl group, and fused ring compounds where only one of the rings is aromatic, such as the 2,3-dihydroindolyl group. Heteroaryl groups may or may not be substituted. Thus, the term "heteroaryl group" includes fused ring compounds and heteroaryl groups having other groups attached to one of the ring members, such as an alkyl group. Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those described above.

[0034] A heterocyclylalkyl group is an alkyl group as defined above, wherein a hydrogen or carbon bond of the alkyl group is replaced by a single bond to a heterocyclyl group as defined above. The heterocyclylalkyl group may or may not be substituted. A substituted heterocyclylalkyl group may be substituted in the alkyl, heterocyclyl or alkyl and heterocyclyl moieties of the group. Representative heterocyclylalkyl groups include, but are not limited to, morpholin-4-yl-ethyl, furan-2-yl-methyl, imidazol-4-yl-methyl, pyridin-3-yl-methyl, tetrahydrofuran-2-yl-ethyl, and indol-2-yl-propyl. Representative substituted heterocyclylalkyl groups may be substituted one or more times with substituents such as those described above.

[0035] A heteroarylalkyl group is an alkyl group as defined above, wherein a hydrogen or carbon bond of the alkyl group is replaced by a single bond to a heteroaryl group as defined above. The heteroarylalkyl group may or may not be substituted. A substituted heteroarylalkyl group may be substituted in the alkyl, heteroaryl or alkyl and heteroaryl moieties of the group. Representative substituted heteroarylalkyl groups may be substituted one or more times with substituents such as those described above.

[0036] Groups described herein having two or more bonds (i.e., divalent, trivalent, or polyvalent) within the compounds of the present technology are named by use of the suffix "ene". For example, a divalent alkyl group is an alkylene group, a divalent aryl group is an arylene group, a divalent heteroaryl group is a divalent heteroarylene group, and the like. Substituents having a single point of attachment to the compounds of the present technology are not applied using the "ene" nomenclature. Thus, for example, chloroethyl is not referred to herein as chloroethylene. Such groups may or may not be substituted.

[0037] An alkoxy group is a hydroxyl group (-OH) in which the bond to the hydrogen atom is replaced by a single bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexyloxy, and the like. Examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy group may or may not be substituted. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those described above.

[0038] As used herein, the terms "alkanoyl" and "alkanoyloxy" can each mean a -C(O)-alkyl and -O-C(O)-alkyl group, respectively, and in some embodiments, the alkanoyl or alkanoyloxy group each contains 2 to 5 carbon atoms. Similarly, the terms "aroyl" and "aroyloxy" each mean a -C(O)-aryl and -O-C(O)-aryl group, respectively.

[0039] The terms "aryloxy" and "arylalkoxy" each mean a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group in which the oxygen atom is bonded to an alkyl, respectively. Examples include, but are not limited to, phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those described above.

[0040] As used herein, the term "carboxylic acid" means a compound having a -C(O)OH group. As used herein, the term "carboxylate" refers to -C(O)O -means a radical. "Protected carboxylate" means -C(O)O-G [wherein G is a carboxylate protecting group]. Carboxylate protecting groups are well known to those skilled in the art. A comprehensive list of protecting groups for carboxylate group functionality can be found in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P.G.M., John Wiley & Sons, New York, NY, (3rd Edition, 1999), which can be added or removed using the procedures described therein and is hereby incorporated by reference in its entirety and for all purposes as if fully set forth herein.

[0041] As used herein, the term "ester" means -COOR 70 radical. R 70 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.

[0042] The term "amide" (or "amido") includes C- and N-amide groups, i.e., -C(O)NR 71 R 72 , and -NR 71 C(O)R 72 radicals. R 71 and R 72 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Thus, amide groups include, but are not limited to, carbamoyl groups (-C(O)NH2) and formamide groups (-NHC(O)H). In some embodiments, the amide is -NR 71 C(O)-(C 1~5is (alkyl), and this group is named "carbonylamino". Otherwise, an amide is -NHC(O)-alkyl, and this group is named "alkanoylamino".

[0043] As used herein, the term "nitrile" or "cyano" means a -CN group.

[0044] The urethane group includes N- and O-urethane groups, i.e., -NR 73 C(O)OR 74 and -OC(O)NR 73 R 74 groups are included. R 73 and R 74 are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. R 73 can also be H.

[0045] As used herein, the term "amine" (or "amino") means a -NR 75 R 76 group [wherein R 75 and R 76 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein]. In some embodiments, the amine is alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH2, methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.

[0046] The term "sulfonamide" includes S- and N-sulfonamide groups, i.e., -SO2NR 78 R 79 and -NR 78 SO2R 79A base is included. R 78 and R 79 are, independently, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. Accordingly, the sulfonamide group includes, but is not limited to only, the sulfamoyl group (-SO2NH2). In some embodiments herein, the sulfonamide is -NHSO2-alkyl and is referred to as an "alkylsulfonylamino" group.

[0047] The term "thiol" means a -SH group, the sulfide includes a -SR 80 group, the sulfoxide includes a -S(O)R 81 group, the sulfone includes a -SO2R 82 group, and the sulfonyl includes a -SO2OR 83 is included. R 80 , R 81 , R 82 and R 83 are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein. In some embodiments, the sulfide is an alkylthio group, -S-alkyl.

[0048] The term "urea" refers to a -NR 84 -C(O)-NR 85 R 86 group. R 84 , R 85 and R 86 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.

[0049] The term "amidine" refers to -C(NR 87 )NR 88 R 89 and -NR 87 C(NR88 )R 89 [wherein, R 87 , R 88 , and R 89 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein] means.

[0050] The term "guanidine" refers to -NR 90 C(NR 91 )NR 92 R 93 [wherein, R 90 , R 91 , R 92 and R 93 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein] means.

[0051] The term "enamine" refers to -C(R 94 )=C(R 95 )NR 96 R 97 and -NR 94 C(R 95 )=C(R 96 )R 97 [wherein, R 94 , R 95 , R 96 and R 97 are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein] means.

[0052] As used herein, the term "halogen" or "halo" means bromine, chlorine, fluorine, or iodine. In some embodiments, the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.

[0053] As used herein, the term "hydroxyl" can mean -OH or its ionized form, -O - .

[0054] The term "imide" means -C(O)NR 98 C(O)R 99 , [wherein R 98 and R 99 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein].

[0055] The term "imine" refers to -CR 100 (NR 101 ) and -N(CR 100 R 101 ) groups [wherein R 100 and R 101 are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, provided that R 100 and R 101 are not both hydrogen at the same time].

[0056] As used herein, the term "nitro" means the -NO2 group.

[0057] As used herein, the term "trifluoromethyl" means -CF3.

[0058] As used herein, the term "trifluoromethoxy" means -OCF3.

[0059] The term "azide" means -N3.

[0060] The term "trialkylammonium" means an -N(alkyl)3 group. The trialkylammonium group has a positive charge and thus usually has an associated anion, such as a halogen anion.

[0061] The term "trifluoromethyldiaziride" means

[0062] [Chemical formula] .

[0063] The term "isocyano" means -NC.

[0064] The term "isothiocyano" means -NCS.

[0065] The term "pentafluorosulfanyl" means -SF5.

[0066] As will be understood by those skilled in the art, for any and all purposes, particularly with regard to providing a written description, all ranges disclosed herein also include any and all possible subranges and combinations of those subranges. Any recited range can be readily recognized as being fully described and such that the same range can be divided into at least equal halves, thirds, fourths, fifths, tenths, etc. By way of non-limiting example, each range discussed herein can be readily divided into a lower third, middle third, and upper third. As will also be understood by those skilled in the art, all language, such as "up to", "at least", "more than", "less than", etc., includes the recited number and then ranges that can be divided into the subranges discussed above. Finally, as will be understood by those skilled in the art, ranges include each individual member. Thus, for example, a group having 1 to 3 atoms means a group having 1, 2, or 3 atoms. Similarly, a group having 1 - 5 atoms means a group having 1, 2, 3, 4, or 5 atoms, etc.

[0067] The pharmaceutically acceptable salts of the compounds described in this specification are within the scope of the present technology, retain the desired pharmacological activity, and are biologically desirable (e.g., the salts are not overly toxic, allergenic, or irritating and are bioavailable), and include acid or base addition salts. When the compounds of the present technology have a basic group, such as an amino group, etc., the pharmaceutically acceptable salts can be formed by inorganic acids (e.g., hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid, etc.), organic acids (e.g., alginic acid, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (e.g., aspartic acid and glutamic acid, etc.). When the compounds of the present technology have an acidic group, such as a carboxylic acid group, etc., this can form salts with metals, such as alkali and alkaline earth metals (e.g., Na + 、Li + 、K + 、Ca 2+ 、Mg 2+ 、Zn 2+ ), ammonia or organic amines (e.g., dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine and ornithine). Such salts can be prepared by reacting the compound during the isolation and purification of the present compound in situ or the purified compound in the form of its free base or free acid with a suitable acid or base separately and isolating the salt thus formed.

[0068] Those skilled in the art will understand that the compounds of the present technology can exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and / or stereoisomerism. Since the diagrams of the formulas within this specification and the claims can represent only one of the possible tautomeric, conformational isomeric, stereochemical, or geometric isomeric forms, the present technology is understood to encompass any tautomeric, conformational isomeric, stereochemical, and / or geometric isomeric forms of the compounds having one or more of the utilities described herein, as well as mixtures of these various different forms.

[0069] "Tautomers" mean isomeric forms of a compound that are in equilibrium with each other. The presence and concentration of the isomeric forms depend on the environment in which the compound is found and can vary, for example, depending on whether the compound is in solid form or in the form of an organic or aqueous solution. For example, in an aqueous solution, quinazolinone can exhibit the following isomeric forms, which are referred to as tautomers of each other.

[0070]

Chem.

[0071]

Chem.

[0072] Since representing a compound by a structural formula is limited, all chemical formulas of the compounds described herein are understood to represent all tautomeric forms of the compound and to be within the scope of the present technology.

[0073] The stereoisomers of the compounds (also known as optical isomers) include all chiral, diastereomeric, and racemic forms of the structure, unless a specific stereochemistry is explicitly indicated. Thus, the compounds used in the present technology include enriched or resolved optical isomers at any or all of the asymmetric atoms, as is apparent from the drawings. Both racemic and diastereomeric mixtures, as well as individual optical isomers, can be isolated or synthesized such that their enantiomeric or diastereomeric partners are substantially absent, and all of these stereoisomers are within the scope of the present technology.

[0074] The compounds of the present technology can exist as solvates, particularly hydrates. Hydrates can be formed during the manufacture of the present compound or a composition containing the present compound, or hydrates can be formed over time due to the hygroscopic nature of the present compound. The compounds of the present technology can also exist as organic solvates, including, among others, DMF, ether, and alcohol solvates. The identification and preparation of any specific solvate are within the skill of those in the art of synthetic organic chemistry or pharmaceutical chemistry.

[0075] Throughout this disclosure, various publications, patents, and published patent specifications are incorporated by reference for identification. Also within the scope of this disclosure, Arabic numerals refer to the references cited, and the full details of the literature are shown to come immediately before the claims. The disclosures of these publications, patents, and published patent specifications are incorporated herein by reference into this disclosure to more fully describe the present technology.

[0076] The present technology Targeted radiotherapy has been carried out for a period of time using macrocyclic complexes of radionuclides. However, the currently used macrocyclic molecules (e.g., DOTA) generally form complexes with insufficient stability with radionuclides, especially radionuclides of larger sizes, such as actinium, radium, bismuth, and lead isotopes. Such instability dissociates the radionuclide from the macrocyclic molecule, thereby resulting in a lack of selectivity for the target tissue, which also leads to toxicity to non-target tissues.

[0077] The present technology provides new macrocyclic complexes that are substantially more stable than those of the prior art. Thus, these new complexes can substantially eliminate toxicity to non-target tissues compared to the complexes in the art and can more efficiently and advantageously target cancer cells. Further, in contrast to DOTA-type complexes that generally require an increase in temperature (e.g., at least 80 °C) for complex formation with radionuclides, the new complexes can advantageously be formed at room temperature. The present technology also particularly uses α-emitting radionuclides instead of β-radionuclides. α-emitting radionuclides have much higher energy and are thus substantially more powerful than β-emitting radionuclides.

[0078] Thus, in one aspect, the compound of formula I is

[0079] [Chem.] [wherein, Z 1 is H or -X 1 -W 2 and Z 2 is OH or NH-W 3 and Z 3 is H or W 7 and; α is 0 or 1; X 1 is O, NH, or S; W 2 and W 3is, independently of each other, H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2) w -R’ (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), or -CH2CH2-(OCH2CH2) x -OR’ (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), and each of them may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2) y -R’ (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), -CH2CH2-(OCH2CH2) z -OR’ (wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W 5 and W 7 are, independently of each other, OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2) w -R’ (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), or -CH2CH2-(OCH2CH2) x -OR’ (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), and each of them may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y x -R’ (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), -CH2CH2-(OCH2CH2) z-OR’ (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or may be substituted with one or more of epoxy groups; R’ is, each occurrence independently, H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C 10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl] or a pharmaceutically acceptable salt thereof is provided.

[0080] Significantly, the unbound form of formula (I) can be combined with radionuclides such as alpha-emitting radionuclides at high radiochemical yields, for example, at least 90%, 95%, 97%, or 98% or above 90%, 95%, 97%, or 98% at room temperature (generally, 18-30 °C, or about 20 °C, about 25 °C, or about 30 °C or below 20 °C, 25 °C, or 30 °C).

[0081] In related aspects, the compound of formula IA is

[0082]

Chemical formula

[0083] In any embodiment disclosed herein, M 1 is actinium-225( 225 Ac 3+ ), radium-223( 233 Ra 2+ ), bismuth-213( 213 Bi 3+ ), lead-212( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149( 149 Tb 3+ ), fermium-255( 255 Fm 3+ ), thorium-227( 227 Th 4+ ), thorium-226( 226 Th 4+ ), astatine-211( 211 At + ), astatine-217( 217 At + ), or may be uranium-230.

[0084] In a further related aspect, the present technology provides a compound (a "targeting compound") useful for targeted radiotherapy of cancer and / or mammalian tissue overexpressing prostate specific membrane antigen ("PSMA"), the compound having the formula II

[0085] [Chemical formula] [wherein M 1 is an α-emitting radionuclide; Z 1 is H or -L 3 -R 22 and Z 2 is OH or NH-L 4 -R 24 and Z 3 is H or -L 6 -R 28 and α is 0 or 1; X 1 is O, NH, or S; L 3 L 4 L 5 or L 6 is, each occurrence independently, a bond or a linker group; R 22 R 24 R 26 and R 28 are each independently an antibody, an antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, a binding polypeptide (e.g., a selective targeting oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase-containing moiety (e.g., an oligonucleotide, a DNA or RNA vector, or an aptamer), or a lectin] or a pharmaceutically acceptable salt thereof.

[0086] In any embodiment disclosed herein that is encompassed by formula II, M 1is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), or uranium-230.

[0087] Representative R 22 , R 24 , R 26 , and R 28 groups include these antibodies described in Table A, as well as antigen-binding fragments of such antibodies, and any equivalent embodiments, as would be known to one of ordinary skill in the art.

[0088]

Table 1

[0089] In any of the embodiments disclosed herein, the binding peptide may comprise a prostate-specific membrane antigen ("PSMA") binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a separase binding compound, or a binding fragment thereof. Exemplary PSMA binding peptides include, but are not limited to, the following structure

[0090]

Chem.

[0091] Somatostatin, which is exemplified in Scheme A, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation through its interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin has two active forms generated by alternative cleavage of a single preproprotein. Five known somatostatin receptors: SST1 (SSTR1); SST2 (SSTR2); SST3 (SSTR3); SST4 (SSTR4); and SST5 (SSTR5) exist, all of which are G protein-coupled seven-transmembrane receptors. Exemplary somatostatin receptor agonists include somatostatin itself, lanreotide, octreotide, octreotide, pasireotide, and vapreotide.

[0092]

Chem.

[0093] Many neuroendocrine tumors express SSTR2 and other somatostatin receptors. Long-acting somatostatin agonists (e.g., octreotide, lanreotide) are used to stimulate the SSTR2 receptor and thus further inhibit tumor growth. See Zatelli MC et al. (April 2007) "Control of pituitary adenoma cell proliferation by somatostatin analogs, dopamine agonists and novel chimeric compounds", European Journal of Endocrinology / European Federation of Endocrine Societies. 156 Suppl 1: S29-35. Octreotide is an octapeptide that mimics natural somatostatin but has a significantly longer half-life in vivo. Octreotide is used for the treatment of tumors that produce growth hormone (acromegaly and gigantism), pituitary tumors that secrete thyroid-stimulating hormone (thyrotropinoma) when surgery is contraindicated, episodes of diarrhea and flushing associated with the carcinoid syndrome, and diarrhea in patients with vasoactive intestinal peptide-secreting tumors (VIPoma). Lanreotide is used for the management of acromegaly and symptoms caused by neuroendocrine tumors, particularly the carcinoid syndrome. Pasireotide is a somatostatin analog with a high affinity for SSTR5 compared to other somatostatin agonists and is approved for the treatment of Cushing's disease and acromegaly. Buserelin is used for the treatment of esophageal variceal bleeding in patients with cirrhosis of the liver and AIDS-related diarrhea.

[0094] Bombesin is a peptide originally isolated from the skin of the European common toad (Bombina bombina). In addition to stimulating gastrin release from G cells, bombesin activates at least three G protein-coupled receptors: BBR1, BBR2, and BBR3, and such activation includes antagonism of such receptors in the brain. Bombesin is also a tumor marker for small cell lung cancer, gastric cancer, pancreatic cancer, and neuroblastoma. Bombesin receptor agonists include, but are not limited to, BBR-1 agonists, BBR-2 agonists, and BBR-3 agonists.

[0095] Seprase (or fibroblast activation protein (FAP)) is an endogenous membrane serine peptidase. In addition to gelatinase activity, seprase has a dual function in tumor progression. Seprase promotes cell invasiveness against the ECM and also supports tumor growth and proliferation. Seprase engagement compounds include seprase inhibitors.

[0096] In a further related aspect, a modified antibody, modified antibody fragment, or modified binding peptide comprising a bond resulting from the conjugation of a compound of formula I or a pharmaceutically acceptable salt thereof to an antibody, antibody fragment, or binding peptide. In related aspects, modified antibodies, modified antibody fragments, or modified binding peptides are provided that comprise a bond resulting from the conjugation of a compound of formula IA or a pharmaceutically acceptable salt thereof to an antibody, antibody fragment, or binding peptide. In any of the embodiments disclosed herein, the antibody can be pembrolizumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, siltuximab, semaprelimab, nivolumab, pembrolizumab, orlatumumab, atezolizumab, avelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, cixutumumab, glembatumumab, nimotuzumab, catumaxomab, or etaracizumab.In any of the embodiments disclosed herein, the antibody fragment may comprise an antigen-binding fragment of belimumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, ofatumumab, obinutuzumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semipramab, nivolumab, pembrolizumab, orlaratumab, atezolizumab, abelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, glembatumumab, nimotuzumab, catumaxomab, or etaracizumab. In any of the embodiments disclosed herein, the binding peptide may comprise a prostate specific membrane antigen ( "PSMA") binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a separase binding compound, or a binding fragment thereof.

[0097] As an example of a modified antibody, modified antibody fragment, or modified binding peptide of the present technology, the binding may be a thiocyanate binding; the thiocyanate binding results from the conjugation of a compound to an antibody, antibody fragment, or binding peptide; the compound is

[0098] [Chemical formula]

[0099] As another example of a modified antibody, modified antibody fragment, or modified binding peptide of the present technology, the binding may be a thiocyanate binding; the thiocyanate binding results from the conjugation of a compound to an antibody, antibody fragment, or binding peptide; the compound is

[0100] [Chemistry]

[0101] In any embodiment herein, the structure may comprise a modified antibody, a modified antibody fragment, or a modified binding peptide that includes a bond resulting from the conjugation of a compound of Formula III, a compound of Formula III or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, a modified antibody, a modified antibody fragment, or a modified binding peptide that includes a bond resulting from the conjugation of a compound of Formula IV, a compound of Formula IV or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, and a target-directed compound of Formula V.

[0102] [Chemistry]

[0103] [Chemistry]

[0104] [Chemistry]

[0105] The target-directed compound of Formula V can be prepared by a process that includes reacting a compound of Formula III or IV with R 22 -W 1 and Table B provides representative examples (wherein n is, independently for each occurrence, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Accordingly, R 22 can be conjugated to the macrocyclic molecule R 1 and W 2 to form a linker L 21 by reaction of the complementary chemical functional groups W 3 . For example, R 22 -W1 It may contain a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A, or an antigen-binding fragment thereof; a PSMA-binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a separase-binding compound, or a binding fragment of any one of them). W 1 W may contain a reactive chemical functional moiety, non-limiting examples of which are disclosed in Table B, W 2 W is the L of formula V 3 It can be selected to react selectively with W 1 so as to provide.

[0106]

Table 2

[0107] In any embodiment herein, the structure may comprise a bond resulting from the conjugation of a compound of formula VI, a compound of formula VI or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, a modified antibody, a modified antibody fragment, or a modified binding peptide, a bond resulting from the conjugation of a compound of formula VII, a compound of formula VII or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, a modified antibody, a modified antibody fragment, or a modified binding peptide, and a target-directed compound of formula VIII.

[0108] [Chemistry]

[0109] [Chemistry]

[0110] [Chemistry]

[0111] The target-directed compound of formula VIII can be prepared by a process comprising reacting a compound of formula VI or VII with R 24 -W 4 and Table C provides representative examples (wherein n is, independently for each occurrence, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Thus, R 24 can be conjugated to the macrocyclic molecule R 3 and W 4 through the reaction of complementary chemical functional groups W 23 to form the linker L 4 . For example, R 24 -W 4 can include a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A, or an antigen-binding fragment thereof; a PSMA-binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase-binding compound, or a binding fragment of any one of them). W 4 can include a reactive chemical functional moiety, non-limiting examples of which are disclosed in Table C, and W 3 can be selected to react selectively with W 4 to provide the L 4 of formula VIII.

[0112] [Table 3] JPEG0007699542000034.jpg125164JPEG0007699542000035.jpg98164

[0113] In any embodiment herein, the structure may comprise a bond resulting from conjugation of a compound of formula IX, a compound of formula IX or a pharmaceutically acceptable salt thereof, to an antibody, antibody fragment, or binding peptide, a modified antibody, modified antibody fragment, or modified binding peptide comprising the bond, a bond resulting from conjugation of a compound of formula X, a compound of formula X or a pharmaceutically acceptable salt thereof, to an antibody, antibody fragment, or binding peptide, a modified antibody, modified antibody fragment, or modified binding peptide comprising the bond, and a target-directed compound of formula XI.

[0114]

Chemical formula

[0115]

Chemical formula

[0116]

Chemical formula

[0117] The target-directed compound of formula XI can be prepared by a process comprising reacting a compound of formula IX or X with R 26 -W 6 Table D provides representative examples (wherein n is, independently for each occurrence, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Thus, R 26 can be conjugated to the macrocyclic molecule R 5 and W 6 by reaction of the complementary chemical functional groups W 25 to form a linker L 5 . For example, R 26 -W 6It may contain a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A, or an antigen-binding fragment thereof; a PSMA-binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a separase-binding compound, or a binding fragment of any one thereof). W 6 W may contain a reactive chemical functional moiety, non-limiting examples of which are disclosed in Table D, and W 5 W is the L of Formula IX 5 and is selected to selectively react with W 6 so as to provide.

[0118] [Table 4] JPEG0007699542000040.jpg87154JPEG0007699542000041.jpg45170

[0119] In any embodiment herein, the structure may comprise a bond resulting from the conjugation of a compound of Formula XII, a compound of Formula XII or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, a modified antibody, a modified antibody fragment, or a modified binding peptide comprising the bond resulting from the conjugation of a compound of Formula XIII, a compound of Formula XIII or a pharmaceutically acceptable salt thereof, to an antibody, an antibody fragment, or a binding peptide, and a target-directed compound of Formula XIV.

[0120] [Chemical Structure]

[0121] [Chemical Structure]

[0122] [Chemical Structure]

[0123] The target-directed compound of formula XIV can be prepared by a process comprising reacting a compound of formula XII or XIII with R 28 -W 8 and Table E provides representative examples (wherein n is, independently for each occurrence, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). Thus, R 28 is conjugated to the macrocyclic molecule R 7 and W 8 by reaction of the complementary chemical functional groups W 27 to form the linker L 4 . For example, R 28 -W 8 may contain a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A, or an antigen-binding fragment thereof; a PSMA-binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a separase-binding compound, or a binding fragment of any one thereof). W 8 may contain a reactive chemical functional moiety, non-limiting examples of which are disclosed in Table E, and W 7 can be selected to react selectively with W 6 to provide the L 8 of formula XIV.

[0124]

Table 5

[0125] Those skilled in the art recognize that a number of chemical conjugation strategies provide easy access to the targeted compounds of the present technology, whereby the exposed amino acid residues of a protein (e.g., an antibody) undergo well-known reactions with the reactive moieties of the complementing molecules. For example, amide coupling is a well-known pathway in which, by way of example, a lysine residue on the surface of an antibody reacts with a terminally activated carboxylic acid ester to form a stable amide bond. Amide coupling is typically mediated by any of several coupling reagents (e.g., HATU, EDC, DCC, HOBT, PyBOP, etc.), which are described in detail elsewhere (see generally Eric Valeur & Mark Bradley, Amide Bond Formation: Beyond the Myth of Coupling Reagents, 38 CHEM. SOC. REV. 606 (2009)). These and other amide coupling strategies have been described in a recent review by Tsuchikama. (Kyoji Tsuchikama & Zhiqiang An, Antibody-Drug Conjugates: Recent Advances in Conjugation and Linker Chemistries, 9 PROTEIN CELL 33, 36 (2018); see also, e.g., A.C. Lazar et al., Analysis of the Composition of Immunoconjugates Using Size-Exclusion Chromatography Coupled to Mass Spectrometry, 19 RAPID COMMUN. MASS SPECTROM. 1806 (2005)).

[0126] Furthermore, those skilled in the art recognize that the cysteine coupling reaction can be utilized to conjugate a molecule lacking a thiol-reactive terminus to the protein surface via the exposed thiol side chain of cysteine residues on the protein (e.g., antibody) surface (generally, see Tsuchikama & An, supra, pp. 36-37; also, see, e.g., Pierre Adumeau et al., Thiol-Reactive Bifunctional Chelators for the Creation of Site-Selectively Modified Radioimmunoconjugates with Improved Stability, 29 BIOCONJUGATE CHEM. 1364 (2018)). Since cysteine residues are more likely to readily form disulfide bonds with neighboring cysteine residues under physiological conditions than to exist as free thiols, some cysteine coupling strategies rely on the selective reduction of disulfides to generate more reactive free thiols (see ibid.). Cysteine coupling techniques known in the art include, but are not limited to, cys alkylation reactions, cysteine re-crosslinking reactions, and cys aryl coupling using organometallic palladium reagents (e.g., see C.R. Behrens et al., Antibody-Drug Conjugates (ADCs) Derived from Interchain Cysteine Cross-Linking Demonstrates Improved Homogeneity and Other Pharmacological Properties Over Conventional Heterogeneous ADCs, 12 MOL. PHARM. 3986 (2015); Vinogradova et al., Organometallic Palladium Reagents for Cysteine Bioconjugation, 526 NATURE 687 (2015); also, see Tsuchikama, supra, p. 37 (consolidated examples)).

[0127] Protein conjugation strategies using non-natural amino acid side chains are also well known in the art. For example, "click chemistry reactions" provide access to conjugated proteins by rapid and selective chemical transformations under a diverse range of reaction conditions. Click chemistry reactions are known to afford peptide conjugates with low by-product formation under aqueous conditions in the presence of unprotected functional groups. An important non-limiting example of a click reaction in the formation of conjugated peptides is the copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction (CuAAC) (see Liyuan Liang & Didier Astruc, The Copper(I)-Catalysed Alkyne-Azide Cycloaddition (CuAAC) “Click” Reaction and Its Applications: An Overview, 255 COORD. CHEM. REV. 2933 (2011); or, for example, Herman S. Gill & Jan Marik, Preparation of 18 F-labeled Peptides using the Copper(I)-Catalyzed Azide-Alkyne 1,3-Dipolar Cycloaddition, 6 NATURE PROTOCOLS 1718 (2011) as well). The CuAAC click reaction can be carried out in the presence of ligands that enhance the reaction rate. Such ligands can include, for example, polydentate nitrogen donors including amines (e.g., tris(triazolyl)methylamine) and pyridine (Liang & Astruc, supra, at 2934 (collective examples); see P. L. Golas et al., 39 MACROMOLECULES 6451 (2006)). Other widely utilized click reactions include, but are not limited to, thiol-ene, oxime, Diels-Alder, Michael addition, and pyridyl sulfide reactions.

[0128] Copper-free (Cu-free) click methods are also useful for drugs for therapy and / or diagnosis, such as radionuclides (e.g., 18F), delivery of chemotherapeutic agents, dyes, contrast agents, fluorescent labels, chemiluminescent labels, or other labels to the protein surface is known in the art. The Cu-free click method may enable stable covalent bonds between target molecules and a family of complementary molecules. The Cu-free click chemical reaction is modified with unnatural amino acid side chains containing activating moieties such as cyclooctynes (e.g., dibenzocyclooctyne (DBCO)), nitrones, or azide groups (e.g., David J. Donnelly et al., Synthesis and Biologic Evaluation of a Novel 18 F-Labeled Adnectin as a PET Radioligand for Imaging PD-L1 Expression, 59 J. NUCL. MED. 529 (2018)), and may include reacting an antibody or antigen-binding fragment presenting a corresponding or complementary reactive moiety such as azide, nitrone, or cyclooctyne (e.g., DBCO) with a family of complementary molecules. For example, if the target-directed molecule contains a cyclooctyne, the family of complementary molecules may include an azide, nitrone, or similar reactive moiety. If the target-directed molecule contains an azide or nitrone, the family of complementary molecules can present a complementary cyclooctyne, alkyne, or similar reactive moiety. The Cu-free click reaction can be carried out in aqueous solution at room temperature in the presence of phosphate buffered saline (PBS). The family of complementary molecules can be radiolabeled (e.g., with 18 F) or conjugated to any other therapeutic and / or diagnostic agent (e.g., a chelating agent) (see ibid., p. 531).

[0129] Compounds of any of the embodiments and aspects herein of the present technology can be trimeric compounds. However, such trimeric compounds are not limited to compositions containing Formula I, IA, or II. Thus, in one aspect, the trimeric compound has a relatively low but still specific affinity for serum albumin for the first domain (e.g., 0.5 to 50×10 -6M), for example, but not limited to only those described in this specification, a second domain containing a chelating moiety, and a third domain containing a tumor targeting moiety (TTT) with a relatively high affinity for a tumor antigen (for example, 0.5 to 50×10 -9 M) are provided. The following exemplary classes of peptide receptors, enzymes, cell adhesion molecules, tumor associated antigens, growth factor receptors, and differentiation antigens are targets useful for constructing the TTT domain: somatostatin peptide receptor-2 (SSTR2), gastrin releasing peptide receptor, seprase (FAP-α), incretin receptor, glucose-dependent insulinotropic polypeptide receptor, VIP-1, NPY, folate receptor, LHRH, and αvβ3, overexpressed peptide receptors, neuronal transporters (for example, norepinephrine transporter (NET)), or other tumor associated proteins, such as EGFR, HER-2, VGFR, MUC-1, CEA, MUC-4, ED2, TF-antigen, endothelial specific markers, neuropeptide Y, uPAR, TAG-72, CCK analogs, VIP, bombesin, VEGFR, tumor specific cell surface proteins, GLP-1, CXCR4, hepsin, TMPRSS2, caspases, Alpha V beta 6, cMET. Other such targets will be apparent to those skilled in the art, and compounds that bind to these can be incorporated into the TTT to generate triple-radiotherapy compounds.

[0130] The following formulas L to LIV provide exemplary general structures for the triple compounds of the present technology.

[0131]

Chemical formula

[0132] In any of the embodiments disclosed herein, the radionuclide is 177 Lu 3+ , 175 Lu 3+ , 45 Sc 3+ , 66 Ga 3+ , 67 Ga 3+ , 68 Ga 3+ , 69 Ga 3+ , 71 Ga 3+ , 89 Y3+ , 86 Y 3+ , 89 Zr 4+ , 90 Y 3+ , 99m Tc +1 , 111 In 3+ , 113 In 3+ , 115 In 3+ , 139 La 3+ , 136 Ce 3+ , 138 Ce 3+ , 140 Ce 3+ , 142 Ce 3+ , 151 Eu 3+ , 153 Eu 3+ , 152 Dy 3+ , 149 Tb 3+ , 159 Tb 3+ , 154 Gd 3+ , 155 Gd 3+ , 156 Gd 3+ , 157 Gd 3+ , 158 Gd 3+ , 160 Gd 3+ , 188 Re +1 , 186 Re +1 , 213 Bi 3+ , 211 At + , 217 At + , 227 Th 4+ , 226 Th 4+ , 225 Ac 3+ , 233 Ra 2+ , 152 Dy 3+ , 213 Bi 3+ ,212 Bi 3+ 、 211 Bi 3+ 、 212 Pb 2+ 、 212 Pb 4+ 、 255 Fm 3+ 、 or may be uranium-230. For example, the radionuclide may be any α-emitting radionuclide, such as 213 Bi 3+ 、 211 At + 、 225 Ac 3+ 、 152 Dy 3+ 、 212 Bi 3+ 、 211 Bi 3+ 、 217 At + 、 227 Th 4+ 、 226 Th 4+ 、 233 Ra 2+ 、 212 Pb 2+ 、 or 212 Pb 4+ may be.

[0133] In any of the embodiments disclosed herein, the triplet compounds of Formulas L-LIV may be those of Formulas LV-LIX.

[0134]

Chemical Formula

[0135] The albumin-binding moiety regulates the rate of plasma clearance of the compound in a subject, thereby increasing the circulation time, and / or compartmentalizes the cytotoxic effect of the cytotoxin-containing domain and / or the imaging ability of the imaging agent-containing domain in the plasma space instead of normal organs and tissues that may express an antigen. Without being bound by theory, this component of the structure is thought to interact reversibly with serum proteins such as albumin and / or cellular elements. The affinity of the albumin-binding moiety for plasma or the cellular components of blood can be configured to affect the residence time of the compound in the blood pool of the subject. In any embodiment herein, the albumin-binding moiety can be configured to bind reversibly or irreversibly to albumin in the case of plasma. In any embodiment herein, the albumin-binding moiety can be selected such that the binding affinity of the compound with human serum albumin is from about 5 μM to about 15 μM.

[0136] By way of example, the albumin-binding moiety of any embodiment herein may include a single-chain fatty acid, a medium-chain fatty acid, a long-chain fatty acid, myristic acid, a substituted or unsubstituted indole-2-carboxylic acid, a substituted or unsubstituted 4-oxo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)butyric acid, a substituted or unsubstituted naphthaleneacylsulfonamide, a substituted or unsubstituted diphenylcyclohexanol phosphate ester, a substituted or unsubstituted 2-(4-iodophenyl)acetic acid, a substituted or unsubstituted 3-(4-iodophenyl)propionic acid, or a substituted or unsubstituted 4-(4-iodophenyl)butyric acid. Some representative examples of albumin-binding moieties that may be included in any embodiment herein are as follows:

[0137] [Chemical formula] One or more of which are included.

[0138] In any embodiment herein, the triple compound is

[0139] [Chemical formula] [wherein Y 501 , Y 502 , Y 503 , Y 504 , and Y 505 are each independently H, halo, or alkyl, X 503 , X 504 , X 505 , and X 506 are each independently O or S, aa is, at each occurrence, independently 0, 1, or 2, bb is, at each occurrence, independently 0 or 1, cc is, at each occurrence, independently 0 or 1, and dd is, at each occurrence, independently 0, 1, 2, 3, or 4]. In any embodiment herein, it may be the case that bb and cc cannot have the same value. In any embodiment herein, Y 503 is I, and Y501 , Y 502 , Y 503 , Y 504 , and Y 505 Each of may independently be H.

[0140] Representative chelators useful in any embodiment of the present technology include, but are not limited to, the following groups: 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), p-SCN-Bn-DOTA (also known as 2B-DOTA-NCS), PIP-DOTA, diethylenetriaminepentaacetic acid (DTPA), PIP-DTPA, AZEP-DTPA, ethylenediaminetetraacetic acid (EDTA), triethylenetetramine-N,N,N’,N’’,N’’’,N’’’-hexa-acetic acid (TTHA), 7-[2-(bis-carboxymethylamino)-ethyl]-4,10-bis-carboxymethyl-1,4,7,10-tetraaza-cyclododec-1-yl-acetic acid (DEPA), 2,2’,2’’-(10-(2-(bis(carboxymethyl)amino)-5-(4-isothiocyanatophenyl)pentyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (3p-C-DEPA-NCS), NETA, {4-carboxymethyl-7-[2-(carboxymethylamino)-ethyl]-perhydro-1,4,7-triazonin-1-yl}-acetic acid (NPTA), diacetylpyridine bis(benzoylhydrazone), 1,4,7,10,13,16-hexaazacyclooctadecane-N,N’,N’’,N’’’,N’’’’,N’’’’’-hexaacetic acid (HEHA), 8-coordinate terephthalamide ligand, Siderophore 2,2'-(4-(2-(Bis(carboxymethyl)amino)-5-(4-isothiocyanatophenyl)pentyl)-10-(2-(bis(carboxymethyl)amino)ethyl)-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid N,N'-Bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (H2macropa) 6-((16-((6-Carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7-yl)methyl)-4-isothiocyanatopicolinic acid (macropa-NCS) 1,4,7,10-Tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane (TCMC) S-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane (S-p-SCN-Bn-TCMC) R-2-(4-Isothiocyanatobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra(2-carbamoylmethyl)cyclododecane (R-p-SCN-Bn-TCMC), and 3,9-Carboxymethyl-6-(2-methoxy-5-isothiocyanatophenyl)carboxymethyl-3,6,9,15-tetraazabicyclo-[9.3.1]pentadeca-1(15),11,13-triene comprises covalently attached substituted or unsubstituted chelators

[0141] Some exemplary elements of this group are illustrated below

[0142]

Chemical Structure

[0143] "Coupled" chelator means a chelator (e.g., as described above), wherein one or more bonds to the hydrogen atoms contained therein are to the remaining atoms of the Rad and / or CHEL moieties, L 501 , and / or L 502 are replaced by a single bond to, or a π bond between two atoms is replaced by a single bond from one of the two atoms to the remaining atoms of the Rad and / or CHEL moieties, L 501 , and / or L 502 and the other of the two atoms includes, for example, a new bond to hydrogen (e.g., reaction of an -NCS group in the chelator to provide a coupled chelator). It should be understood that

[0144] In any of the embodiments disclosed herein, the CHEL of the triple compound can be a chelator as shown in the compounds of Formula I, IA, or II. For example, the triple compound can be a target-directed compound of Formula II (wherein R 22 , R 24 , R 26 , and R 28 are each independently

[0145]

Chemical formula

[0146] In any of the embodiments disclosed herein, TTT is

[0147]

Chemical formula

[0148] In any embodiment herein, P 501 、P 502 、and P 503 can each be H.

[0149] The triple compounds of the present technology include variations of any of three domains: for example, a domain containing a chelator, a domain containing an albumin - binding group, or a domain containing a tumor - targeting moiety. The following is exemplary.

[0150] RPS - 092.

[0151]

Chemical formula

[0152] In any embodiment disclosed herein, RPS - 92 can optionally 213 Bi 3+ 、 211 At + 、 225 Ac 3+ 、 152 Dy 3+ 、 212 Bi 3+ 、 211 Bi 3+ 、 217 At + 、 227 Th 4+ 、 226 Th 4+ 、 233 Ra 2+ 、 212 Pb 2+ 、or 212 Pb 4+ chelate.

[0153] NTI-093 is an analog of NTI-063, and TCMC is used as a chelator.

[0154]

Chemical formula

[0155] In any of the embodiments disclosed herein, NTI-93 may, in some cases, 212 Pb 2+ or 212 Pb 4+ chelate.

[0156] NTI-094 is an analog of NTI-072, and TCMC is used as a chelator.

[0157]

Chemical formula

[0158] In any of the embodiments disclosed herein, NTI-94 may, in some cases, 212 Pb 2+ or 212 Pb 4+ chelate.

[0159] Next is a bromo analog of NTI-063 with a modified albumin-binding domain.

[0160]

Chemical formula

[0161] Next is a chloro analog of NTI-063 with a modified albumin-binding domain.

[0162]

Chemical formula

[0163] NTI-309 modifies a tumor targeting domain to target sepulase (fibroblast activation protein / FAP).

[0164]

Chemical formula

[0165] The NTI-309 compound can include TCMC as a chelator.

[0166]

Chemical formula

[0167] In any of the embodiments disclosed herein, NTI-309 may, in some cases, 212 Pb 2+ or 212 Pb 4+ chelate.

[0168] Next is a boronic acid analog of NTI-309.

[0169]

Chemical formula

[0170] Next is a boronic acid analog of NTI-309 using TCMC as a chelator.

[0171]

Chemical formula

[0172] In any of the embodiments disclosed herein, this analog may, in some cases, 212 Pb 2+ or 212 Pb 4+ chelate.

[0173] As a further specific example, a derivative of RPS-072 (which itself targets PSMA) can be constructed, TTT has an affinity for the SSTR2 receptor using a derivative of a ranlactotide, and this compound (A) has a molecular weight of 3537.93, and C 165 H 235 IN 28 O 44 has the formula of S3. Similarly, a derivative of RPS-072 that targets the GRP / bombesin receptor can be prepared, and this compound (B) has a molecular weight of 3537.93, and C 167 H 248 IN 31 O 44 has the formula of S.

[0174]

Chemical Structure

[0175] The present technology also provides a composition (e.g., a pharmaceutical composition) and a medicament comprising any one embodiment of a compound of formula I, IA, II, a modified antibody of the present technology disclosed herein, a modified antibody fragment, or a modified binding peptide disclosed herein, or a triple compound disclosed herein, and a pharmaceutically acceptable carrier or one or more additives or fillers (collectively referred to as "pharmaceutically acceptable carrier" unless otherwise specified). The composition can be used in the methods and treatments described herein. The pharmaceutical composition can comprise an effective amount of any embodiment of a compound of the present technology for treating cancer and / or mammalian tissue overexpressing PSMA, or an effective amount of any embodiment of a modified antibody, modified antibody fragment, or modified binding peptide of the present technology for treating cancer and / or mammalian tissue overexpressing PSMA, or an effective amount of any embodiment of a triple compound of the present technology for treating cancer and / or mammalian tissue overexpressing PSMA. In one aspect, a method of treating a subject is provided, comprising administering to the subject a targeting compound of the present technology, or administering to the subject a modified antibody, modified antibody fragment, or modified binding peptide of the present technology. In any embodiment disclosed herein, the subject may have a problem of cancer and / or mammalian tissue overexpressing prostate specific membrane antigen ("PSMA"). In any embodiment herein, the administering step may comprise administering an effective amount of any embodiment of a compound of the present technology for treating cancer and / or mammalian tissue overexpressing PSMA of the compound, or an effective amount of any embodiment of a modified antibody, modified antibody fragment, or modified binding peptide of the present technology for treating cancer and / or mammalian tissue overexpressing PSMA, or an effective amount of any embodiment of a triple compound of the present technology for treating cancer and / or mammalian tissue overexpressing PSMA.The subject may have problems with mammalian tissues that express somatostatin receptors, bombesin receptors, separase, or any combination of two or more thereof, and / or mammalian tissues that overexpress PSMA. The mammalian tissues of any of the embodiments disclosed herein can include one or more of tumors that produce growth hormone, neuroendocrine tumors, pituitary tumors, vasoactive intestinal peptide-secreting tumors, small cell lung cancer, gastric cancer, pancreatic cancer, neuroblastoma, and metastatic cancer. In any of the embodiments disclosed herein, the subject may have one or more problems with glioma, breast cancer, adrenocortical cancer, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer. In any of the embodiments disclosed herein, the composition (e.g., pharmaceutical composition) and / or medicament can be formulated for parenteral administration. In any of the embodiments disclosed herein, the composition (e.g., pharmaceutical composition) and / or medicament can be formulated for intravenous administration. In any of the embodiments disclosed herein, the administration step of the method can include parenteral administration. In any of the embodiments disclosed herein, the administration step of the method can include intravenous administration.

[0176] In any of the above embodiments, the effective amount can be determined for a subject. The "effective amount" means the amount of a compound or composition required to produce a desired effect. Non-limiting examples of an effective amount include, but are not limited to, amounts or dosages that result in acceptable toxicity levels and bioavailability levels for therapeutic (pharmaceutical) use, including the treatment of one or more of glioma, breast cancer, adrenocortical cancer, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer. Another example of an effective amount includes, for example, amounts or dosages that can reduce the symptoms associated with one or more of glioma, breast cancer, adrenocortical cancer, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer, such as reducing the growth and / or metastasis of prostate cancer, breast cancer, or bladder cancer. The effective amount can be from about 0.01 μg to about 1 mg of the compound per gram of the composition, preferably from about 0.1 μg to about 500 μg of the compound per gram of the composition. As used herein, "subject" or "patient" is a mammal, such as a cat, dog, rodent, or primate. Usually, the subject is a human, preferably a human having or suspected of having one or more problems of glioma, breast cancer, adrenocortical cancer, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer (e.g., colon adenocarcinoma), primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer. The terms "subject" and "patient" can be used interchangeably.

[0177] In any of the embodiments of the present technology described herein, the pharmaceutical composition can be packaged in unit dosage forms. The unit dosage forms are effective in treating one or more of glioma, breast cancer, adrenocortical cancer, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer (e.g., colon adenocarcinoma), primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer. Generally, the unit dosage forms, including the compounds of the present technology, vary according to the considerations for the patient. Such considerations include, for example, age, protocol, condition, gender, degree of disease, contraindications, combination therapies, etc. Exemplary unit dosage forms based on these considerations may also be adjusted or modified by a physician skilled in the art. For example, the unit dosage form for a patient containing the compound of the present technology can range from 1×10 -4 g / kg to 1 g / kg, preferably from 1×10 -3 g / kg to 1.0 g / kg. The dosage of the compound of the present technology can also range from 0.01 mg / kg to 100 mg / kg, preferably from 0.1 mg / kg to 10 mg / kg. Suitable unit dosage forms include, but are not limited to, powders, tablets, pills, capsules, troches, suppositories, patches, nasal sprays, injections, implantable sustained-release formulations, mucoadherent films, topical varnishes, lipid complexes, etc.

[0178] The pharmaceutical composition can be prepared by mixing one or more of the compounds of Formula I, IA, II, or any one of the modified antibodies, modified antibody fragments, or modified binding peptides of the present technology, or any embodiment of the triple compounds of the present technology, pharmaceutically acceptable salts thereof, their stereoisomers, their tautomers, or their solvates, with pharmaceutically acceptable carriers, additives, binders, excipients, etc., to prevent and treat cancer and / or disorders associated with mammalian tissues overexpressing PSMA. Using the compounds and compositions described herein, formulations and pharmaceuticals for treating, for example, prostate cancer, breast cancer, or bladder cancer can be prepared. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions. The present composition can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or by an implantable reservoir. Parenteral administration or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular injections. The following dosage forms are shown by way of example and should not be construed as limiting the instant present technology of the invention.

[0179] For oral, buccal, and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gel capsules, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the technology of the present invention, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive, such as starch or other additives. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers or glycerides. In some cases, oral dosage forms can contain other components that assist in administration, such as inert excipients, or lubricants, such as magnesium stearate, or preservatives, such as parabens or sorbic acid, or antioxidants, such as ascorbic acid, tocopherol or cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavoring agents or flavoring agents. Tablets and pills can be further processed with suitable coating materials known in the art.

[0180] Liquid dosage forms for oral administration can be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which can contain inert excipients, such as water and the like. Pharmaceutical formulations and pharmaceuticals can be prepared as liquid suspensions or solutions using sterile liquids, such as, but not limited to, oils, water, alcohols, and combinations thereof. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents can be added for oral or parenteral administration.

[0181] As described above, the suspension can contain oil. Such oil includes, but is not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. The suspension formulation can also contain esters of fatty acids, for example, ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. The suspension formulation can contain alcohols, for example, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers, for example, but not limited to, poly(ethylene glycol), petroleum hydrocarbons, for example, mineral oil and petrolatum; and water can also be used in the suspension formulation.

[0182] Injectable dosage forms generally include aqueous suspensions or oily suspensions, which can be prepared using suitable dispersing or wetting agents and suspending agents. The injectable form can be in the form of a solution or a suspension, and is prepared with a solvent or excipient. Acceptable solvents or vehicles include sterile water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oil can be used as a solvent or suspending agent. Usually, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

[0183] In the case of injection, the pharmaceutical formulation and / or drug can be a powder suitable for reconstitution with the appropriate solution described above. Examples of these include, but are not limited to, lyophilized, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or microparticles. In the case of injection, the formulation can optionally contain stabilizers, pH adjusters, surfactants, bioavailability modifiers and combinations thereof.

[0184] The compounds of the present technology can be administered to the lungs by inhalation through the nose or mouth. Suitable pharmaceutical formulations for inhalation include solutions, sprays, dry powders, or aerosol agents containing any suitable solvent, and optionally, other compounds such as, but not limited to, stabilizers, antibacterial agents, antioxidants, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof. Carriers and stabilizers vary depending on the required amount of the specific compound, but typically include non-ionic surfactants (Tween, Pluronic, or polyethylene glycol), harmless proteins such as serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, saccharides, or sugar alcohols. Aqueous and non-aqueous (e.g., in the form of fluorocarbon propellants) aerosol agents are commonly used for the delivery of the compounds of the present technology by inhalation.

[0185] In addition to these typical dosage forms described above, pharmaceutically acceptable additives and carriers are well known to those skilled in the art and are thus included in the technology of the present invention. Such additives and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991), which is hereby incorporated by reference into this specification. The composition can also include, for example, micelles or liposomes, or some other encapsulated form.

[0186] Specific dosages can be adjusted according to the subject's disease state, age, weight, general health, gender, and diet, dosing interval, route of administration, excretion rate, as well as the combination of drugs. Any of the above dosage forms containing an effective amount are sufficient within the scope of routine experimentation and are thus sufficient within the scope of the technology of the present invention.

[0187] Various assays and model systems can be readily used to determine the therapeutic efficacy of the treatment according to the present technology.

[0188] In the case of the state shown, the test subject shows a 10%, 20%, 30%, 50% or more reduction, a reduction up to 75 - 90%, or a 95% or more reduction in one or more symptoms (s) caused by or associated with the disorder in the subject, as compared to a placebo - treated or other appropriate control subject.

[0189] In other aspects, the technology provides a method of treating cancer by administering to a subject having cancer an effective amount of a targeting composition according to formula (II). Since the cancer cell targeting agent can be selected to target any of a wide range of cancers, the cancers contemplated herein for treatment are not limited. The cancer can be essentially any type of cancer. For example, an antibody or peptide vector can be generated to target any of a wide range of cancers. The targeting compositions described herein are typically administered by injection into the bloodstream, but other modes of administration, such as oral or topical administration, are also contemplated. In some embodiments, the targeting composition can be administered locally, at the site where the target cells are present, i.e., in a particular tissue, organ, or body fluid (e.g., blood, cerebrospinal fluid, etc.). Any cancer that can be delivered to the target through the bloodstream is specifically contemplated herein. Some examples of applicable body sites containing cancer cells include the breast, lung, stomach, intestine, prostate, ovary, cervix, pancreas, kidney, liver, skin, lymph, bone, bladder, uterus, colon, rectum, and brain. The cancer can also include the presence of one or more carcinomas, sarcomas, lymphomas, blastomas, or teratomas (germ cell tumors). The cancer can also be in the form of leukemia. In some embodiments, the cancer is triple - negative breast cancer.

[0190] As is well known in the art, the dosage of the active ingredient(s) generally depends on the disorder or condition to be treated, the degree of the disorder or condition, the method of administration, the size of the patient, and potential side effects. In different embodiments, depending on these and other factors, the appropriate dosage of the targeted composition can be exactly, at least, for example, at least 1 mg, 10 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, or 1500 mg, more than 1 mg, 10 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, or 1500 mg, up to or less than 1 mg, 10 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1200 mg, or 1500 mg, or within a range limited by any of the exemplary dosages described above. Further, the composition can be administered in any suitable schedule, for example, once, twice, or three times a day or on alternate days for the entire treatment period of 1, 2, 3, 4, or 5 days, or 1, 2, 3, or 4 weeks, or 1, 2, 3, 4, 5, or 6 months, or within the time frame therebetween, in the indicated amounts. Alternatively, or additionally, the composition can be administered until the desired change in the disorder or condition is achieved or when a preventive effect is considered to be provided.

[0191] The examples in this specification are provided to illustrate the benefits of the present technology and to further assist those skilled in the art by preparing or using the compounds of the present technology or their salts, pharmaceutical compositions, derivatives, prodrugs, or tautomers thereof. The examples in this specification are also shown to more fully illustrate the preferred embodiments of the present technology. These examples should not be construed as limiting the scope of the present technology as defined by the appended claims. These examples can include or incorporate any variation, aspect, or embodiment of the present technology described above. The aforementioned variations, aspects, or embodiments can also include or incorporate variations of any or all other variations, aspects, or embodiments of the present technology.

Example

[0192] Exemplary Synthetic Procedures and Characterizations Materials and Instrumentation Used. All solvents and reagents were purchased from commercial sources and used without further purification when administered, unless otherwise indicated. Solvents labeled “dry” were obtained after storage over 3 Å molecular sieves. Metal salts were purchased from Strem Chemicals (Newburyport, MA), obtaining the highest purity available; Lu(ClO4)3 was provided as an aqueous solution containing 15.1 wt% Lu. The bifunctional ligand p-SCN-Bn-DOTA was purchased from Macrocyclics (Plano, TX). NMe4OH was purchased as a 25 wt% solution in H2O (trace metal basis, Beantown Chemical, Hudson, NH). Hydrochloric acid (BDH Aristar Plus, VWR, Radnor, PA) and nitric acid (Optima, ThermoFisher Scientific, Waltham, MA) were of trace metal grade. 225Chelex 100 (sodium form, 50 - 100 mesh) and human serum used for the Ac-complex challenge assay were purchased from Sigma Aldrich (St. Louis, MO). Deionized water (≥18 MΩcm) was prepared on-site using a Millipore Direct-Q® 3UV or an Elga Purelab Flex 2 water purification system.

[0193] The reaction was monitored by thin layer chromatography (TLC, Whatman UV254 aluminum-backed silica gel). The HPLC system used for the analysis and purification of the compounds consisted of a CBM-20A communication bus module, an LC-20AP (preparative) or LC-20AT (analytical) pump, and an SPD-20AV UV / Vis detector monitoring at 270 nm (Shimadzu Corporation, Japan). Analytical chromatography was carried out at a flow rate of 1.0 mL / min using an Ultra Aqueous C18 column, 100 Å, 5 μm, 250 mm × 4.6 mm (Restek, Bellefonte, PA), unless otherwise indicated. Purification was carried out at a flow rate of 14 mL / min using an Epic Polar preparative column, 120 Å, 10 μm, 25 cm × 20 mm (ES Industries, West Berlin, NJ), unless otherwise indicated. Gradient HPLC methods were used with a binary mobile phase containing H2O (A) and MeOH (B) or ACN (C). HPLC Method A: 10% B (0 - 5 min), 10 - 100% B (5 - 25 min). Method B: 10% C (0 - 5 min), 10 - 100% C (5 - 25 min). Method C: 10% C (0 - 5 min), 10 - 100% C (5 - 40 min). Method D: 10% C (0 - 5 min), 10 - 100% C (5 - 20 min). The solvent systems contained 0.1% trifluoroacetic acid (TFA), except for Method C which used 0.2% TFA. NMR spectra were recorded at ambient temperature on a Varian Inova 300 MHz, 400 MHz, 500 MHz or 600 MHz spectrometer, or a Bruker AV III HD 500 MHz spectrometer equipped with a broadband Prodigy cryoprobe. Chemical shifts were reported in ppm. 1 H and 13 1H and 13C NMR spectra were referenced to an internal standard of TMS (0 ppm), the remaining solvent peaks, or an internal standard of acetonitrile (2.06 ppm in the D2O spectrum). 19 19F NMR spectra were referenced to an internal standard of monofluorobenzene (-113.15 ppm). The reported 1The splitting of proton resonances in the H spectrum is defined as s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dt = triply degenerate doublet, td = doubly degenerate triplet, and br = broad. IR spectroscopy was performed on KBr pellets of the samples using a Nicolet Avatar 370 DTGS (ThermoFisher Scientific, Waltham, MA). High-resolution mass spectra (HRMS) were recorded in positive ESI mode on an Exactive Orbitrap mass spectrometer (ThermoFisher Scientific, Waltham, MA). UV / Vis spectra were recorded on a Cary 8454 UV-Vis (Agilent Technologies, Santa Clara, CA) using 1-cm quartz cuvettes unless otherwise indicated. Elemental analysis (EA) was performed by Atlantic Microlab, Inc. (Norcross, GA).

[0194] Synthesis and characterization of the Macropa complex, Macropa-NCS, and Macropa-NHC(S)NHCH3. N,N'-bis[(6-carboxy-2-pyridyl)methyl]-4,13-diaza-18-crown-6 (H2macropa·2HCl·4H2O) [102,103] was purchased from EMD Millipore (Darmstadt, Germany) or prepared using 1,7,10,16-tetraoxa-4,13-diazacyclooctadecane (7) synthesized according to the literature protocol

[0104] Potassium cerium(IV) sulfate monohydrate (1) was purchased from TCI America (Portland, OR). Dimethyl 4-chloropyridine-2,6-dicarboxylate (2),

[0105] dimethyl 4-azidopyridine-2,6-dicarboxylate (3),

[0106] and methyl 6-chloromethylpyridine-2-carboxylate (8),

[0102] were prepared according to the indicated literature protocols.

[0195] [La(macropa)] 2+ Preparation.

[0196]

Chem.

[0197] [Lu(macropa)] + Preparation.

[0198]

Chem.

[0199] Preparation of dimethyl 4-aminopyridine-2,6-dicarboxylate (4).

[0200]

Chemical formula

[0201] Preparation of ethyl 4-amino-6-(hydroxymethyl)picolinate (5).

[0202]

Chem.

[0203] Preparation of ethyl 4-amino-6-(chloromethyl)picolinate (6).

[0204]

Chem.

[0205] Preparation of methyl 6-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7-yl)methyl)picolinate (9·2TFA·1H2O).

[0206]

Chem.

[0207] Preparation of ethyl 4-amino-6-((16-((6-(methoxycarbonyl)pyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7-yl)methyl)picolinate (10).

[0208]

Chem.

[0209] Preparation of 4-amino-6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7-yl)methyl)picolinic acid (11·4TFA).

[0210] [Chemical formula] Compound 10 (0.612 g) was dissolved in 6 M HCl (7 mL) and heated at 90 °C for 17 h. The dark brown solution containing a slight precipitate was concentrated under reduced pressure at 60 °C to a light yellowish brown solid. To this solid was added 10% MeOH / H2O containing 0.1% TFA (3 mL). The slight suspension was filtered and the filtrate was purified by preparative HPLC using Method A. The pure fractions were combined, concentrated under reduced pressure at 60 °C, and then lyophilized to give 11 as an off-white solid (0.2974 g, 46% yield over 2 steps). 1 H NMR (500 MHz, DMSO-d6) δ = 8.13 - 8.08 (m, 2H), 7.80 (dd, J = 7.3, 1.6 Hz, 1H), 7.64 (br s), 7.24 (d, J = 2.3 Hz, 1H), 6.76 (d, J = 2.3 Hz, 1H), 4.74 (s, 2H), 4.15 (s, 2H), 3.85 (t, J = 5.0 Hz, 4H), 3.63 (t, J = 5.1 Hz, 4H), 3.57 - 3.50 (m, 12H), 3.09 (br t, J = 5.2 Hz, 4H). 13 C{ 1 H} NMR (126 MHz, DMSO-d6) δ 165.96, 163.37, 159.47, 158.78 - 157.98 (q, TFA), 151.93, 151.64, 148.25, 144.68, 139.59, 128.43, 124.96, 120.79 - 113.68 (q, TFA), 109.40, 108.96, 70.03, 69.89, 67.09, 65.16, 57.28, 55.85, 54.47, 53.81. 19 F NMR (470 MHz, DMSO-d6) δ = -74.03. EA found: C, 40.60; H, 4.29; N, 7.04. C 26 H 37 N5O 8·Calculated values for 4CF3COOH: C, 40.69; H, 4.12; N, 6.98. IR (cm -1 ): 3387, 3161, 1735, 1670, 1204, 1130, 791, 722. HPLC t R = 11.974 min (Method B); 11.546 min (Method D). HRMS (m / z): 548.26883 [M + H] + ; calculated value: 548.27149.

[0211] Preparation of 6 - ((16 - ((6 - carboxypyridin - 2 - yl)methyl)-1,4,10,13 - tetraoxa - 7,16 - diazacyclooctadecane - 7 - yl)methyl)-4 - isothiocyanatopicolinic acid (12, macropa - NCS).

[0212] [Chemical formula] A white suspension of 11 (0.1598 g, 0.16 mmol) and Na2CO3 (0.2540 g, 2.4 mmol) was heated under reflux in acetone (10 mL) for 30 min, and then CSCl2 (305 μL of CSCl2, 85%, Acros Organics) was added slowly. The resulting orange suspension was heated under reflux for 3 h and then concentrated under reduced pressure at 30 °C to a pale orange solid. The solid was dissolved little by little in 10% ACN / H2O containing 0.2% TFA (total 8 mL), filtered, and immediately purified by preparative HPLC using Method C.

[0108] The pure fractions were combined, concentrated under reduced pressure at RT to remove the organic solvent, and then lyophilized. Fractions that could not be concentrated immediately were frozen at - 80 °C. Isothiocyanate 12 was obtained as a mixture of white and pale yellow solids (0.0547 g) and stored at - 80 °C in a wide - mouth bottle with Drierite. From the 1 H NMR and 19 F NMR spectra of samples of 12 added with known concentrations of fluorobenzene, it was estimated that 12 was isolated as the tetra - TFA salt. 11H NMR (400 MHz, DMSO-d6) δ = 8.17 - 8.06 (m, 2H), 8.00 (s w / fine splitting, 1H), 7.84 (d, J = 1.5 Hz, 1H), 7.81 - 7.75 (d w / fine splitting, J = 7.16 Hz, 1H), 4.71 (s, 2H), 4.64 (s, 2H), 3.89 - 3.79 (m, 8H), 3.62 - 3.46 (m, 16H). 19 19F NMR (470 MHz, DMSO-d6) δ = -74.17. IR (cm -1 ): ~3500 - 2800, 2083, 2026, 1735, 1670, 1591, 1448, 1183, 1130, 796, 717. HPLC t R = 15.053 min (Method B); 13.885 min (Method D). HRMS (m / z): 590.22600 [M + H] + ; calculated: 590.22791.

[0213] Preparation of 6 - ((16 - ((6 - carboxypyridin - 2 - yl)methyl)-1,4,10,13 - tetraoxa - 7,16 - diaza - cyclooctadecane - 7 - yl)methyl)-4-(3 - methylthioureido)picolinic acid (13, macropa - NHC(S)NHCH3).

[0214]

Chem.

[0215] Preparation of Macropa-(OCH2CH2)-Ph-NCS. A schematic overview of the synthesis of another embodiment of Macropa-NCS with improved stability is provided in Figure 3. This compound is evaluated as described below and is useful for chelation of radionuclides to antibodies, antibody fragments (e.g., antigen-binding fragments), and peptides, as well as for the manufacture of therapeutic compounds and its inevitable use in targeted delivery of therapeutic radiation. Detailed information on the synthesis is provided below.

[0216]

Chemical formula

[0217]

Chemical formula

[0218]

Chemical formula

[0219]

Chemical formula

[0220] [Chemical Formula] To a stirred solution of Compound 6 (0.205 g, 0.5 mmol) and diisopropylethylamine (0.129 g, 1 mmol) in dry ACN (10 mL), Compound 5 (0.233 g, 0.5 mmol) in dry ACN (2 mL) was added. The resulting ionic solution was stirred at room temperature for 12 h. The solvent was removed and the crude compound was purified by combiflash using MeOH in DCM to afford Compound 7.

[0221] [Chemical Formula] Compound 7 (0.08 g, 0.1 mmol) was dissolved in 6 M aqueous HCl (5 mL) and stirred at room temperature for 2 h to 3 h. After completion of the starting material (as indicated by LCMS), the aqueous HCl was removed under reduced pressure and the crude reaction mixture containing Compound 8 was used in the next step of the synthesis without further purification.

[0222] [Chemical Formula] The crude deboc product was dissolved in THF: 1M LiOH (1:1, 5 mL) and stirred until the reaction was complete. The resulting crude product was purified by prep-HPLC to give Compound 9.

[0223]

Chemical formula

[0224]

Chemical formula

[0225] X-ray diffraction tests. Single crystals of H2macropa·2HCl·4H2O suitable for X-ray diffraction were allowed to stand at room temperature and then grown from a saturated H2O: acetone (1:5) solution. Single crystals of [La(Hmacropa)(H2O)]·(ClO4)2 were grown by vapor diffusion of THF into an acidic aqueous solution (pH approximately 2) after addition of the complex. Single crystals of [Lu(macropa)]·ClO4·DMF were grown by vapor diffusion of Et2O into a DMF solution of the complex.

[0226] X-ray diffraction data for H2macropa·2HCl·4H2O, [La(Hmacropa)(H2O)]·(ClO4)2, and [Lu(macropa)]·ClO4·DMF were collected at 223 K on a Bruker APEX 2 CCD Kappa diffractometer (Mo Kα, λ = 0.71073 Å). These structures were analyzed by the intrinsic phasing method using SHELXT

[0109] and after establishing an improved strategy, SHELXL

[0110] Precision was carried out for all data by full - matrix least squares using 2 with respect to 2 .

[0111] All non - hydrogen atoms were refined anisotropically. Hydrogen atoms were included in the model at geometrically calculated positions and refined using the riding model. Hydrogen atoms bonded to nitrogen and oxygen were located by difference Fourier synthesis and subsequently refined semi - freely using distance restraints. The isotropic displacement parameters of all hydrogen atoms were fixed at 1.2 times the U value of the atoms to which they are linked (1.5 times in the case of methyl groups). In the case of [La(Hmacropa)(H2O)]·(ClO4)2, the partially occupied solvent molecules of water were included in the unit cell but could not be satisfactorily modeled. Therefore, this solvent was treated as a contribution to the overall scattering by diffusion without using the positions of specific atoms, by means of the solvent masking function in Olex2.

[0112]

[0227] La by Macropa 3+ and Lu 3+ titrations. The pH of 10 mM 3 - (N - morpholino)propanesulfonic acid (MOPS) buffer was adjusted to 7.4 using an aqueous solution of NMe4OH. The ionic strength was set at 100 mM using NMe4Cl. Stock solutions of LaCl3·6.8H2O (40 mM) and LuCl3·6H2O (21 mM) were prepared with 1 mM HCl. A stock solution of H2macropa·2HCl·4H2O (8.8 mM) was prepared in MOPS buffer. Titration solutions containing macropa (100 μM) and LaCl3 or LuCl3 were prepared in MOPS from these stock solutions. Each metal ion titration was carried out at RT by adding 5 - 10 μL aliquots of the titrant to a cuvette containing 3000 μL of macropa (100 μM) in MOPS. Each sample was equilibrated for 5 minutes each time before adding to acquire the spectrum. The complex formation of the metal ions was monitored by the decrease in absorbance at 268 nm, which is the λ max of macropa. The titrant was added until no further spectral changes were detected.

[0228] La of Macropa 3+ and Lu 3+ Kinetic Inertness of Complexes: The Transchelation Challenge. Stock solutions of ethylenediaminetetraacetic acid (EDTA, 100 mM) were prepared in MOPS buffer (prepared as described above) by adjusting the pH of the initial suspension to 6.6 using aqueous NMe4OH. Stock solutions of diethylenetriaminepentaacetic acid (DTPA, 125 mM) were prepared in H2O by adjusting the pH to 7.4 as described for EDTA. This solution was serially diluted with H2O to produce 12.5 mM and 1.25 mM solutions of DTPA.

[0229] Preformed La of macropa 3+ and Lu 3+ complexes were challenged with EDTA. The challenge was initiated by adding aliquots of a solution containing EDTA (98.7 mM) and macropa (100 μM) in MOPS buffer to each solution of the complexes. The final M:macropa:EDTA ratios were approximately 1:1:20 (La) and 1:1:10 (Lu). The solutions were repeatedly analyzed by UV spectroscopy over 21 days for any spectral changes. The final pH of each solution was between 7.18 and 7.25.

[0230] La 3+ and in situ formed complexes between macropa were further severely challenged with excess DTPA. A solution containing 500 μM of the complex, prepared using the aforementioned LaCl3 and macropa stock solutions, was equilibrated for 5 minutes. Subsequently, this was divided into cuvettes and diluted with 125 mM DTPA, 12.5 mM DTPA, 1.25 mM DTPA, or MOPS to produce solutions containing 1000-, 100-, 10-, or 0-fold excess DTPA and 100 μM concentration of macropa. These solutions were repeatedly analyzed by UV spectroscopy over 21 days for any spectral changes. The final pH of each solution was between 7.11 and 7.42.

[0231] Macropa and DOTA 225 Ac radioisotope label. 225 Ac and 225 Ra were produced by the fission reaction of uranium carbide and separated downstream from other radionuclides by a mass separator using the isotope separation and accelerator (ISAC: Isotope Separator and Accelerator) online isotope separation (ISOL) capabilities at TRIUMF (Vancouver, BC, Canada), and collected according to the literature protocol. [103,104] Next, 225 Ac was separated from [105,106] Ra by a DGA column 225 (branched, 50 - 100 μm, Eichrom Technologies LLC) and obtained in 0.05 M HNO3 for use in radioisotope labeling experiments. Aluminum-backed TLC plates (silica gel 60, F 254 , EMD Millipore, Darmstadt, Germany) were used to 225 analyze the progress of the Ac radioisotope labeling reaction. Instant thin layer chromatography paper impregnated with silica gel (iTLC-SG, Agilent Technologies, Mississauga, ON, Canada) was used for 3+ La and serum stability challenges. The TLC plates were developed and then counted in a BioScan System 200 imaging scanner equipped with a BioScan Autochanger 1000 and WinScan software after at least 8 h to allow the daughter isotopes to fully decay and ensure that the measured radioactivity signal was generated by the parent 225 Ac. 225 Ac, 221 Fr, and 213 quantitative radioactivity measurements of Bi were performed using NIST-traceable mixed 133 Ba and 152Determined by γ-spectrometry using a high-purity germanium (HPGe) detector (Canberra GR1520, Meriden, CT) calibrated with a Eu source. The dead time of the detector was maintained below 10% for all measurements. The data were analyzed using Genie2000 software (v3.4, Canberra, Meriden, CT).

[0232] Concentration dependence. Various concentrations of macropa and DOTA were radiolabeled with 225 Ac 3+ to determine the lowest concentration at which >95% radiolabeling further occurred. Stock solutions of H2macropa·2HCl·4H2O (10 -3 ~10 -8 M) and H4DOTA (10 -3 、10 -5 、and 10 -7 M) were prepared in H2O. For each radiolabeling reaction, the ligand (10 μL) and 225 Ac (10 - 26 kBq, 10 - 30 μL) were sequentially added to NH4OAc buffer (pH 6, 0.15 M, 150 μL) to obtain final ligand concentrations of 5.3×10 -5 ~5.9×10 -10 M for macropa and 5.9×10 -5 ~5.9×10 -9 M for DOTA. The final pH of all labeling reactions was between 5.5 and 6. The reaction solution was maintained at ambient temperature or at 80 °C. The progress of the reaction was monitored at 5 and 30 minutes by spotting 3 - 5 μL of the reaction solution on TLC plates. These plates were developed with a mobile phase of 0.4 M sodium citrate (pH 4) containing 10% MeOH and then counted. Under these conditions, 225 Ac(macropa)] + and 225 Ac(DOTA)] - stayed at the baseline (R F = 0), and any unchelated 225 Ac( 225 Ac-citrate) migrated with the solvent front (R F=1). Radiochemical yields (RCYs) were determined by integrating the peak areas in the radiochromatogram and 225 Ac-complex (R F =0) associated counts were calculated by dividing by the total counts integrated along the length of the TLC plate.

[0233] Macropa and DOTA's 225 Ac complex kinetic inertness.

[0234] Summary. Stock solutions of La(NO3)3 (0.001 M or 0.1 M) were prepared in H2O. Macropa (10 -5 M stock solution 10 μL; 1.0×10 -10 mol) or DOTA (10 -3 M stock solution 10 μL; 1.0×10 -8 mol) and 225 Ac (10 μL, 26 kBq) containing radioactive labeled samples were added with a 50-fold molar excess of La 3+ (5 μL of 0.001 M or 0.1 M stock solution was added to the solutions containing macropa and DOTA, respectively). The solutions were maintained at room temperature and analyzed by iTLC at several time points over 8 days. The iTLC plates were developed using citric acid (0.05 M, pH 5) as the eluent. Under these conditions, 225 Ac(macropa)] + and 225 Ac(DOTA)] - remained at the baseline (R F =0), and any unchelated 225 Ac( 225 Ac-citrate) migrated with the solvent front (R F =1). The percentage of the complex remaining unchanged was determined by integrating the peak areas in the radiochromatogram and 225 Ac-complex (R F =0) associated counts were calculated by dividing by the total counts integrated along the length of the iTLC plate.

[0235] La 3+ transmetalation reaction by 225 Ac(macropa)] + and 225 Ac(DOTA)] - were prepared using 10 -5 M and 10 -3 M stock solutions (10 μL) of macropa and DOTA, respectively, to obtain final ligand concentrations of 5.9×10 -7 M (macropa) and 5.9×10 -5 M (DOTA). After confirming a radiochemical yield >90% by TLC using 0.4 M sodium citrate (pH 4) containing 10% MeOH as the mobile phase, 160 μL of human serum (equal volume based on the labeling reaction volume) was added to each radiolabeled solution. A control solution was also prepared, substituting water for the ligand. The solutions were monitored by iTLC over 8 days. The plates were developed with EDTA (50 mM, pH 5) as the eluent. Under these conditions, 225 Ac(macropa)] + and 225 Ac(DOTA)] - complexes remained at the baseline (R F = 0), and any 225 Ac( 225 Ac-EDTA) that was transchelated by the serum migrated with the solvent front (R F = 1). The percentage of the complex remaining unchanged was calculated.

[0236] In vivo biodistribution of the 225 Ac complexes of Macropa and DOTA. All experiments were approved by the Institutional Animal Care Committee (IACC) of the University of British Columbia and were conducted in accordance with the Canadian Council on Animal Care Guidelines. A total of 9 female C57BL / 6 mice (6 - 8 weeks old, 20 - 25 g) were used for the biodistribution studies of each radiometal complex, with n = 3 at each time point.

[0237] Macropa (100 μL out of 1 mg / mL solution in NH4OAc) was diluted with 387 μL of NH4OAc (1 M, pH 7), and then 225 an aliquot (203 μL) of Ac(NO3)3 (approximately 157 kBq) was added; the pH of this solution was adjusted to 6.5 - 7 by adding 1 M NaOH (210 μL, trace metal grade). After 5 minutes at ambient temperature, the reaction solution was analyzed by TLC (using 0.4 M sodium citrate (pH 4) as the eluent), which confirmed a radiochemical yield > 95%. The reaction was allowed to proceed overnight, and it was confirmed that the radiochemical yield was again > 95% the next morning. During this period, the mice were anesthetized with 2% isoflurane, 225 Ac(macropa)] + and approximately 100 μL (10 - 15 kBq) of the complex was injected into the tail vein of each mouse. After injection, the mice were allowed to recover and move freely in their cages, and were euthanized by CO2 inhalation 15 minutes, 1 hour, or 5 hours after injection (n = 3 for each time point). Blood was collected by cardiac puncture and placed in appropriate tubes for scintillation measurement. The collected tissues included heart, liver, kidney, lung, small intestine, large intestine, brain, bladder, spleen, stomach, pancreas, bone, thyroid, tail, urine, and feces. The tissues were weighed and then counted using a calibrated gamma counter (Packard, Cobra II model 5002) with three energy windows: 60 - 120 keV (window A), 180 - 260 keV (window B), and 400 - 480 keV (window C). The measurements were performed immediately after sacrifice and 7 days later; the counts were decay-corrected from the time of injection and then converted to percentage of injected dose per gram of tissue (%ID / g). Differences between the data were not shown; thus, the in vivo distribution was reported using the data obtained immediately with window A.

[0238] 225 Ac(DOTA)] - and 225 the in vivo distribution studies of Ac(NO3)3 were performed with the following modifications, 225 Ac(macropa)] + ​It was carried out as described above. 225 Ac(DOTA)] - was prepared by adding 225 Ac(NO3)3 (338 μL, 1.1 MBq) to a solution of DOTA (100 μg, 20 mg / mL in H2O) in NH4OAc (467 μL, 0.15 M, pH 7). The pH of the solution was adjusted to 7 using NH4OAc (150 μL, 1 M, pH 7), and the solution was heated at 85 °C for 45 minutes. An RCY > 99% was confirmed by TLC as described above. 225 Ac(DOTA)] - was diluted with saline to a final concentration of 0.05 MBq / 100 μL, and 100 μL was injected into each mouse. 225 Ac(NO3)3 (approximately 58 μL, 0.4 MBq) was diluted and 225 Ac(DOTA)] - was injected in the same manner. 225 Ac(DOTA)] - One mouse that was euthanized at the 5 h time point during the test died immediately after injection. In the same manner, 225 one mouse that was euthanized at the 1 h time point during the Ac(NO3)3 test died.

[0239] Hydrolysis of Macropa-NCS and p-SCN-Bn-DOTA. Approximately 1 mg of macropa-NCS (Compound 12, n = 4) or p-SCN-Bn-DOTA (n = 5) was added to a screw-cap vial containing 1 mL of 0.1 M NaHCO3 buffer (pH 9.1) containing 0.154 M NaCl, which had been passed through a pre-equilibrated Chirex column. After stirring for 1 minute, each solution was filtered through a 0.2 μm PES or PTFE membrane. 5 μL aliquots were removed from the vial at various time points over 46 - 72 h and analyzed by HPLC. Method D was used for macropa-NCS. Method B was used for p-SCN-Bn-DOTA with an Epic Polar C18 column, 120 Å, 10 μm, 25 cm × 4.6 mm (ES Industries, West Berlin, NJ) at a flow rate of 1 mL / min. Between samplings, the vials were stored at room temperature (23 ± 1 °C) away from light. Hydrolysis was considered complete after the peak at 13.8 min (corresponding to 12) or 18.417 min (corresponding to p-SCN-Bn-DOTA) had disappeared or had negligible integration. In the linear regression performed with a plot of ln peak area vs. time, the pseudo-first-order rate constant (k obs ) was shown as a negative slope. The half-life (t 1 / 2 ) was calculated using the equation t 1 / 2 = 0.693 / k obs . The half-life of each compound was reported as the mean ± 1 standard deviation.

[0240] La 3+ Titration of Macropa-NHC(S)NHCH3 conjugate with La 3+The titration of macropa-NHC(S)NHCH3 conjugate (13) was carried out at pH 7.4 for macropa. The amount of ACN in the sample did not exceed 3.3% by volume. After adding each aliquot, a waiting time of 3 minutes was found to be sufficient for the sample to reach equilibrium before spectral acquisition. The complex formation of metal ions was monitored using the increase in absorbance at 300 nm. The pH of the solution at the end of the titration was 7.43.

[0241] Kinetic Inactivation of La-Macropa-NHC(S)NHCH3: The Transchelation Challenge. Solutions of diethylenetriaminepentaacetic acid (DTPA; 125 mM and 12.5 mM) were prepared in MOPS buffer (pH 7.4). A MOPS solution containing macropa-NHC(S)NHCH3 (126.7 μM, 16.7% by ACN volume) and LaCl3 (126.2 μM) was prepared using the aforementioned stock solutions and equilibrated for 10 minutes. Subsequently, this was divided into cuvettes and diluted with 125 mM DTPA, 12.5 mM DTPA, or MOPS to produce solutions containing 1000-, 100-, or 0-fold excess DTPA. The final concentration of macropa-NHC(S)NHCH3 in each cuvette was 25.3 μM. These solutions were repeatedly analyzed by UV spectroscopy over 21 days for any spectral changes. The final pH of each solution was between 7.42 and 7.49. The experiment was conducted 3 times.

[0242] 225 Exemplary Synthesis and Bioactivity of Ac-macropa-RPS-070.

[0243] Preparation of di-tert-butyl (((S)-1-(tert-butoxy)-6-(3-(3-ethynylphenyl)ureido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (214).

[0244]

Chemical Structure

[0247] and isolated as an off-white powder. 1 H NMR (500 MHz, CDCl3) δ= 7.90 (s, 1H), 7.58 (t, 1H, J = 1.7 Hz), 7.51 (dd, 1H, J1= 8.2 Hz, J2= 1.3 Hz), 7.18 (t, 1H, J = 7.9 Hz), 7.05 (d, 1H, J = 7.7 Hz), 6.38 (d, 1H, J = 7.9 Hz), 6.28 (br s, 1H), 5.77 (d, 1H, J = 6.9 Hz), 4.32 (m, 1H), 4.02 (m, 1H), 3.53 (m, 1H), 3.05 (m, 1H), 3.00 (s, 1H), 2.39 (m, 2H), 2.07 (m, 1H), 1.88 (m, 1H), 1.74 (m, 1H), 1.62 (m, 1H), 1.49-1.37 (m, 4H), 1.41 (s, 18H), 1.37 (s, 9H).

[0245] 2,5-dioxopyrrolidin-1-yl N 2 -(((9H-fluoren-9-yl)methoxy)carbonyl)-N 6 -(tert-butoxycarbonyl)-L-lysinate (215) was prepared.

[0246] [Chemical formula] A suspension of Fmoc-L-Lys(Boc)-OH (5.0 g, 10.7 mmol) and N,N'-disuccinimidyl carbonate (2.74 g, 10.7 mmol) in CH2Cl2 (50 mL) was stirred at room temperature under argon. Then, DIPEA (1.86 mL, 10.7 mmol) was added and the suspension was stirred overnight. The solvent was evaporated under reduced pressure and the crude product was purified by flash chromatography (0 - 100% EtOAc in hexane). Lysine 215 was isolated as a white powder (2.5 g, 41%). 11H NMR (500 MHz, CDCl3) δ = 7.76 (d, 2H, J = 7.6 Hz), 7.59 (d, 2H, J = 7.3 Hz), 7.40 (t, 2H, J = 7.4 Hz), 7.32 (t, 2H, J = 7.3 Hz), 5.46 (br s, 1H), 4.71 (m, 2H), 4.45 (m, 2H), 4.23 (t, 1H, J = 6.6 Hz), 3.14 (br s, 2H), 2.85 (s, 4H), 2.02 (m, 1H), 1.92 (m, 1H), 1.58 (m, 4H), 1.44 (s, 9H).

[0247] tert-Butyl N 2 -(N 2 -(((9H-Fluoren-9-yl)methoxy)carbonyl)-N 6 -(tert-Butoxycarbonyl)-L-lysyl)-N 6 -((Benzyloxy)carbonyl)-L-lysinate(216) preparation.

[0248]

Chemical Structure

[0249] Preparation of 2,5-dioxopyrrolidin-1-yl 2-(4-iodophenyl)acetate (217).

[0250]

Chemical Structure

[0251] tert-Butyl N 2 -(N 2-(1-Azido-3,6,9,12,15,18-hexaoxaheneicosan-21-yl)-N 6 -(tert-Butoxycarbonyl)-L-lysyl)-N 6 -((Benzyloxy)carbonyl)-L-lysinate(218) Preparation.

[0252] [Chemical formula] To a solution of Fmoc-protected dilysine 216 (768 mg, 0.97 mmol) in CH2Cl2 (4 mL) was added NHEt2 (2.07 mL, 20 mmol). The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the crude product, which was a yellow oil, was used without further purification. To a solution of this oil (183 mg, 0.32 mmol) in CH2Cl2 (3 mL) were sequentially added a solution of NEt3 (57 μL, 0.41 mmol) in CH2Cl2 (1 mL) and a solution of azido-PEG6-NHS ester (100 mg, 0.21 mmol; Broadpharm, USA) in CH2Cl2 (1 mL), and the reaction mixture was stirred overnight at room temperature. It was then diluted with CH2Cl2 and washed sequentially with H2O and saturated NaCl solution. The organic layer was dehydrated over MgSO4, filtered, and concentrated under reduced pressure to give azido 218 as a colorless oil (184 mg; 95%) without further purification. Mass (ESI+): 926.4 [M+H] + . Mass calculated value = 925.54.

[0253] Di-tert-butyl (((S)-1-(tert-butoxy)-6-(3-(3-(1-((9S,12S)-9-(tert-butoxycarbonyl)-12-(4-((tert-butoxycarbonyl)amino)butyl)-3,11,14-trioxo-1-phenyl-2,17,20,23,26,29,32-heptaoxa-4,10,13-triazatetratriacontan-34-yl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate(219) Preparation.

[0254] [Chem.] A DMF (0.5 mL) solution of 100 μL of 0.5 M CuSO4 and 100 μL of 1.5 M sodium ascorbate was mixed for 5 minutes and then added to a DMF (2.5 mL) solution of 218 (184 mg, 0.20 mmol) and 214 (132 mg, 0.21 mmol). The resulting mixture was stirred at room temperature for 45 minutes. It was then concentrated under reduced pressure, and the crude residue was purified by flash chromatography (0 - 30% MeOH in EtOAc) to give triazole 219 as a pale yellow oil (285 mg; 87%). Mass (ESI+): 1557.2 [M+H] + . Calculated mass = 1555.90.

[0255] Preparation of di-tert-butyl ((((S)-1-(tert-butoxy)-6-(3-(3-(1-((23S,26S)-26-(tert-butoxycarbonyl)-23-(4-((tert-butoxycarbonyl)amino)butyl)-33-(4-iodophenyl)-21,24,32-trioxo-3,6,9,12,15,18-hexaoxa-22,25,31-triazatritriacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)-1-oxohexan-2-yl)carbamoyl)-L-glutamate (220).

[0256] [Chem.] Cbz-protected triazole 219 (285 mg, 0.18 mmol) was dissolved in MeOH (15 mL) in a two-necked flask. To the solution was added 10% Pd / C (20 mg), the suspension was shaken, and the flask was evacuated. Then, the suspension was placed under a H2 atmosphere and stirred overnight. It was filtered through Celite, and the filter cake was washed three times with MeOH. The combined filtrate was concentrated under reduced pressure and used without further purification to obtain the free amine as a colorless oil (117 mg; 45%). Mass (ESI+): 1423.8 [M+H] + . To a solution of amine (117 mg, 82 μmol) in CH2Cl2 (4 mL) was added a solution of DIPEA (23 μL, 131 mmol) in CH2Cl2 (1 mL), and the mixture was stirred at room temperature under argon. Then, a solution of 217 (37 mg, 103 μmol) in CH2Cl2 (2 mL) was added, and the reaction was stirred at room temperature for 2 h. Then, it was poured into H2O (10 mL), and the layers were separated. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product as a colorless semi-solid. The crude product was purified by prep TLC (10% MeOH in EtOAc) to obtain phenyl iodide 220 as a colorless oil (34 mg; 25%). Mass (ESI+): 1666.6 [M+H] + . Mass calculated = 1665.80.

[0257] (((S)-1-Carboxy-5-(3-(3-(1-((23S,26S)-26-carboxy-23-(4-(3-(2-carboxy-6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7-yl)methyl)pyridin-4-yl)thioureido)butyl)-33-(4-iodophenyl)-21,24,32-trioxo-3,6,9,12,15,18-hexaoxa-22,25,31-triazatritriacontyl)-1H-1,2,3-triazol-4-yl)phenyl)ureido)pentyl)carbamoyl)-L-glutamic acid (221, macropa-RPS-070) preparation.

[0258]

Chem.

[0259] 225 Preparation of the radiosynthesis of Ac-macropa-RPS-070.

[0260] General. All reagents were purchased from Sigma Aldrich and were reagent grade unless otherwise indicated. Hydrochloric acid (HCl) was traceSELECT® (>99.999%) for trace element analysis quality. Aluminum-backed silica thin layer chromatography (TLC) plates were purchased from Sigma Aldrich. Stock solutions of 0.05 M HCl and 1 M NH4OAc were prepared by dilution in Milli-Q® water.

[0261] Radiolabeling procedure. 225To a 0.05 M HCl (17.9 MBq in 970 μL) solution of Ac(NO3)3 (Oak Ridge National Laboratory, USA), 20 μL of a 1 mg / mL solution of macropa-RPS-070 in DMSO was added. The pH was raised to 5 - 5.5 by adding 90 μL of 1 M NH4OAc. The reactants were left at room temperature for 20 minutes while shaking periodically. Then, 200 μL of the reaction solution was removed and diluted with 3.8 mL of commercially available physiological saline (0.9% NaCl in de-H2O; VWR) to obtain a solution at a concentration of 910 kBq / mL. An aliquot was removed from the final solution and spotted on an aluminum-backed silica TLC plate to determine the radiochemical yield. In 0.05 M HCl 225 An aliquot of the Ac(NO3)3 solution was spotted in a parallel lane as a control. The plate was immediately developed in a 10% v / v MeOH / 10 mM EDTA mobile phase and then left standing for 8 h to allow radiochemical equilibrium to be achieved. The plate was exposed on a fluorescence surface for 3 minutes and then visualized on a Cyclone Plus Storage Phosphor System (Perkin Elmer). The radiochemical yield was 225 expressed as a ratio to the total activity of Ac-macropa-RPS-070 and was determined to be 98.1%.

[0262] 225 In vivo distribution study of Ac-macropa-RPS-070.

[0263] Cell culture. The PSMA-expressing human prostate cancer cell line, LNCaP, was obtained from the American Type Culture Collection. Cell culture supplies were from Invitrogen unless otherwise indicated. LNCaP cells were maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum (Hyclone), 4 mM L-glutamine, 1 mM sodium pyruvate, 10 mM N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid (HEPES), 2.5 mg / mL D-glucose, and 50 μg / mL gentamicin in a humidified incubator at 37 °C / 5% CO2. Cells were removed from the flask for transfer or passage to a 12-well assay plate by incubating them with 0.25% trypsin / ethylenediaminetetraacetic acid (EDTA).

[0264] Inoculation of xenografts into mice. All animal studies were approved by the Institutional Animal Care and Use Committee of Weill Cornell Medical College and were conducted in accordance with the guidelines described in the USPHS Policy on Humane Care and Use of Laboratory Animals. Animals were housed under standard conditions in an approved facility with a 12 h light / dark cycle. Food and drinking water were provided ad libitum throughout the duration of the study. Male hairless nu / nu mice were purchased from the Jackson Laboratory. For inoculation in mice, LNCaP cells were suspended at 4 × 10 7 cells / mL in a 1:1 mixture of PBS:Matrigel (BD Biosciences). Each mouse was injected with 0.25 mL of the cell suspension into the left flank. Biodistribution was performed when the tumors were in the range of 100 - 400 mm 3 .

[0265] In LNCaP xenograft mice 225In Vivo Distribution of Ac-macropa-RPS-070. Fifteen mice bearing LNCaP xenograft tumors (5 per time point) were intravenously injected with a bolus injection of each ligand at 85 - 95 kBq and 100 ng (50 pmol). The mice were sacrificed by cervical dislocation at 4, 24, and 96 h after injection. Blood samples were removed, and a complete in vivo distribution study was performed on the following organs (including contents): heart, lung, liver, small intestine, large intestine, stomach, spleen, pancreas, kidney, muscle, bone, and tumor. The tissues were weighed and counted on a 2470 Wizard automatic gamma counter (Perkin Elmer). 1% ID / mL samples were counted before and after each set of tissue samples to allow for attenuation correction. The count values were corrected for attenuation and the injected activity, and tissue uptake was expressed as percent injected dose per gram (% ID / g). Standard error measurements were calculated at each data point.

[0266]

Table 6

[0267] Conjugation of Macropa-NCS and p-SCN-Bn DOTA to Trastuzumab.

[0268] General. All glassware was washed overnight in 1 M HCl. Saline (0.154 M NaCl) and all buffers were passed through a PD-100 column pre-equilibrated with the appropriate buffer. Trastuzumab (Tmab, Genentech) was purified with saline as the mobile phase using a Zeba spin desalting column (2 mL or 5 mL, 40 MWCO, Thermo Scientific, Waltham, MA) according to the manufacturer's protocol. The concentration of the purified Tmab was calculated by the Lambert-Beer law using 280 and ε 280 1.446 mL mg -1 cm -1 as used.

[0107] The purified Tmab and Tmab conjugate were stored at 4°C.

[0269] Conjugation of Macropa-NCS to Tmab. A stock solution containing Macropa-NCS (12) at 4.4 mg / mL was prepared in 0.1 M pH 9.1 NaHCO3 buffer containing 0.154 M NaCl and stored at -80°C. The stability of 12 during storage was verified by analytical HPLC. To a portion of Tmab in saline (74 μL), 12 (52 μL) and NaHCO3 buffer (266 μL) were added such that the final concentrations of Tmab and 12 were 5.1 mg / mL and 0.59 mg / mL, respectively. Macropa-NCS was estimated to be a 16-fold molar excess over Tmab based on a molecular weight of 1045.76 g / mol for 12 (tetra-TFA salt). The pH of this solution was between 8 and 9 as determined by litmus test paper. The solution was gently agitated at room temperature for 17.5 h and then purified using a spin column.

[0270] Conjugation of p-NCS-Bn-DOTA to Tmab. A stock solution containing p-NCS-Bn-DOTA at 3.05 mg / mL was prepared in H2O and stored at -80°C. To a portion of Tmab in saline (66 μL), p-NCS-Bn-DOTA (49 μL) and NaHCO3 buffer (274.5 μL) were added such that the final concentrations of Tmab and p-NCS-Bn-DOTA were 5.1 mg / mL and 0.38 mg / mL (16-fold molar excess of L), respectively. The pH of this solution was between 8 and 9 as determined by litmus test paper. The solution was gently agitated at room temperature for 17.5 h and then purified using a spin column.

[0271] Determination of the complex protein concentration by BCA assay. The protein concentration in the Macropa-Tmab and DOTA-Tmab conjugates was determined using the Pierce™ BCA Protein Assay Kit (Thermo Scientific, Waltham, MA, microplate protocol). Tmab was used as the protein standard. The stock solution of purified Tmab was diluted with saline, and the concentration of this solution (1.83 mg / mL) was determined using a NanoDrop 1000 spectrophotometer (Thermo Scientific, Waltham, MA). The standard curve was linear over the measured concentration range (0 - 1828 μg / mL) (r 2 = 0.9966). The protein concentration of each conjugate was calculated from two independent dilutions, measured three times each, and the results were averaged to obtain a protein concentration of 4.557 mg / mL for macropa-Tmab and 2.839 mg / mL for DOTA-Tmab.

[0272] Analysis of the ligand-to-protein ratio by MALDI-ToF. The average number of macropa or DOTA ligands conjugated to Tmab was determined by MALDI-ToF MS / MS on a Bruker autoflex speed at the Alberta Proteomics and Mass Spectrometry Facility (University of Alberta, Canada) using the procedures described elsewhere.

[0108] The purified Tmab and these conjugates were analyzed twice, and the [M+H] + mass signals obtained from the chromatograms were averaged for each compound. The ligand-to-protein (L:P) ratio for each conjugate was obtained by subtracting the molecular weight of Tmab from the molecular weight of the conjugate and then dividing by the mass of the bifunctional ligand.

[0273] Tmab conjugate 225 Ac radiolabeling and serum stability of the complex.

[0274] Summary. The progress of the Ac radiolabeling reaction was monitored and serum stability was determined using instant thin layer chromatography paper impregnated with silica gel (iTLC-SG, Agilent Technologies, Mississauga, ON, Canada). 225 The TLC plates were developed as described below and then counted in a BioScan System 200 imaging scanner equipped with a BioScan Autochanger 1000 and WinScan software after at least 8 h to completely decay the time for the daughter isotope and ensure that the measured radioactivity signal was generated by the parent 225 Ac.

[0275] 225 Ac radiolabeling test. In a total reaction volume of 200 μL prepared with NH4OAc buffer (pH 6, 0.15 M), 225 Ac (10 or 20 kBq, 7 - 10 μL) was mixed with macropa-Tmab (5.5 - 22 μL) or DOTA-Tmab (8.81 - 35.2 μL) 25 - 100 μg, and the pH was adjusted to approximately 5 with NaOH. A control solution was also prepared in which unmodified Tmab (25 μg) was substituted in place of the conjugate. The reaction solution was maintained at ambient temperature and analyzed at 5 min, 30 min, 1 h, 2 h, 3 h, and 4 h by spotting 8 μL three times on an iTLC strip. The strip was developed with a mobile phase of 0.05 M citric acid (pH 5). Under these conditions, 225 Ac-macropa-Tmab and 225 Ac-DOTA-Tmab remained at the baseline of the plate (R F = 0), and any unchelated 225 Ac ( 225 Ac-citrate) migrated with the solvent front (R F = 1). The radiochemical yields (RCYs) were calculated by integrating the peak area under the curve in the radiochromatogram and dividing the counts associated with the 225 Ac-complex (R F = 0) by the total counts integrated along the length of the TLC plate.

[0276] In human serum 225 Stability of Ac-macropa-Tmab. 225 A solution of Ac-macropa-Tmab was prepared using 100 μg of protein. After confirmation by TLC where RCY>95% was achieved, human serum was thawed at room temperature and added to the radiolabeled immune complex to obtain a solution containing 90% serum by volume. The samples were incubated at 37 °C. At various time points over 7 days, aliquots (15 - 30 μL) were removed from the samples and spotted 3 times on iTLC strips. The strips were developed using an EDTA (50 mM, pH 5.2) mobile phase and counted. Under these conditions, 225 Ac-macropa-Tmab remained at the baseline (R F = 0), and any 225 Ac( 225 Ac-EDTA) migrated with the solvent front (R F = 1). The percentage of complex remaining unchanged was calculated.

[0277] As an additional challenge, separate aliquots (39 μL) were also removed from the serum samples on day 1 and day 7 and mixed with 50 mM DTPA (pH 7, 13 μL) to challenge any 225 Ac that was only loosely bound by the radioimmuno complex to dissociate. After incubating this solution at 37 °C for 15 minutes, aliquots (30 μL) were spotted 3 times on an iTLC plate and developed using an EDTA (50 mM, pH 5.2) mobile phase. The percentage of complex remaining unchanged was calculated.

[0278] 225 Ac(macropa)] + , 225 Ac(DOTA)] - , and 225 In vivo biodistribution study of Ac(NO3)3.

[0279]

Table 7

[0280]

Table 8

[0281]

Table 9

[0282] 225 In vivo test of Ac-macropa-Tmab.

[0283] At the time points shown in Table 4 below, aliquots of the complex in serum were removed and analyzed directly by radio-TLC or first mixed with an excess of DTPA to remove any loosely bound 225 Ac. The decay-corrected values shown represent the % activity associated with the complex at R F = 0 on the TLC plate after exposure to the EDTA mobile phase. The reported uncertainty (±1SD) was derived from spotting three TLC plates at each time point. The % of unchanged complex remaining was not significantly different (p > 0.05, two-sided t-test) for samples challenged with DTPA compared to samples not challenged with DTPA. These results demonstrate that 225 Ac remains strongly bound by macropa-Tmab in human serum over 7 days.

[0284]

Table 10

[0285] Characterization of an 18-membered macrocyclic ligand for ion chelation Radium-223( 223 Ra) is the first therapeutic alpha (α)-emitting radionuclide approved for clinical use in cancer patients and is effective in eradicating bone metastases. To take advantage of the therapeutic potential of α-particles for soft tissue metastases, a strategy of targeted alpha-particle therapy (TAT) has been elucidated, in which a lethal α-emitting radionuclide is conjugated to a tumor-targeting vector using a bifunctional chelator to selectively deliver cytotoxic α-radiation to cancer cells. Actinium-225( 225 Ac) has a 10-day long half-life that is suitable for antibody-based targeting vectors and produces four high-energy α-emissions that are extremely lethal to cells, so it was tested for use in TAT. The 12-membered tetraaza macrocyclic molecule H4DOTA is currently 225 Ac 3+ the state of the art for ion chelation, but when the ionic radius of the metal ion increases, the thermodynamic stability of the H4DOTA complex decreases, and this ligand is shown to be not optimal for its chelation of Ac 3+ ions (the largest +3 ions in the periodic table). The macrocyclic complexes of the present technology show significant and unexpected improvements compared to known complexes, and in this example (H2macropa and H2macropa-NCS; Scheme 1), improved 225 Ac bifunctional chelators according to the present technology are exemplified.

[0286] Scheme 1. Structures of H2macropa, H2macropa-NCS (“macropa-NCS”), and macropa-(OCH2CH2)-Ph-NCS.

Chemical formula

[0287] Previous tests have shown that macropa, which evaluates the thermodynamic affinity for the entire lanthanide series, is smaller than Lu3+ , Ca 2+ , and Cm 3+ It was shown to be selective for larger metal ions La 3+ , Pb 2+ , and Am 3+ compared to the ions. [24-26] Without being bound by theory, it was considered that macropa should efficiently chelate large Ac 3+ ions. Prior to evaluating its Ac-chelation properties, complex formation was evaluated in situ between macropa and cold La 3+ and Lu 3+ ions. In these tests, La 3+ was used as a non-radioactive surrogate for Ac because it is chemically similar despite being slightly smaller (1.03 Å, CN6). 225 Complex formation of the smaller Lu 3+ ions (0.861 Å, CN6) by macropa was investigated to explore its size-selectivity. The high affinity of these metal ions for macropa at pH 7.4 was confirmed by La 3+ and Lu 3+ titrations. This is consistent with the previously measured stability constants (log K 3+ = 14.99, log K LaL = 8.25). LuL The kinetic inertness of these in situ-formed complexes was investigated by challenging them with an excess of ethylenediaminetetraacetic acid (EDTA) or diethylenetriaminepentaacetic acid (DTPA) chelators that have a higher thermodynamic affinity for Lu

[24] and La 3+ ions than macropa. 3+ The Lu

[27] ions were transchelated within 1 minute even with the addition of only 10 equivalents of EDTA, while the La 3+ complex remained unchanged for 21 days in the presence of 1000 equivalents of DTPA. These results show that La 3+ complexes 3+Despite the fact that DTPA strongly thermodynamically favors the transchelation of , the high level of kinetic inertness of the macropa complex has been demonstrated to suppress this process on a detectable time scale.

[0288] La of macropa 3+ and Lu 3+ complexes were isolated and their solid structures were elucidated by X-ray crystallographic analysis (Figs. 1A - 1D). La 3+ and Lu 3+ ions are present in the above 18-membered macrocyclic molecule, and the two picolinate arms are located on the same side of the macrocyclic molecule. For Lu 3+ the coordination sphere of the ion is filled by 10 donors of macropa where both picolinate arms are deprotonated; in contrast, the larger La 3+ ion forms an 11-coordinate complex by the incorporation of inner-sphere water molecules that penetrate through the macrocyclic molecule. Due to recent EXAFS studies demonstrating that Ac 3+ prefers an 11 coordination number in aqueous solution, the ability of macropa to form stable 11-coordinate complexes is of particular importance. [29,30]

[0289] Macropa was tested for the chelation of the larger, radioactive 225 Ac 3+ ions and compared to DOTA. Both ligands (59 μM) were incubated in 0.15 M NH4OAc buffer at pH 5.5 - 6 with 225 Ac (26 kBq), and the complex formation reaction was monitored by radio-TLC after 5 minutes. Surprisingly, macropa formed complexes with all of the 225 Ac within just 5 minutes at RT, while DOTA was only 10% bound under these conditions. At a concentration 100 times lower (0.59 μM) of macropa, which has an L:M ratio of only 1800, the radiolabeling was even more complete at 5 minutes at RT. At this concentration, DOTA was 225Failed to form a complex with Ac. In summary, these tests have revealed that macropa exhibits excellent radiolabeling kinetics at ambient temperature and ligand concentrations below μM, under conditions where DOTA fails.

[0290] 225 The long half-life of Ac, due to its stable complex retention in vivo, avoids off-target damage to normal tissues resulting from the release of free 225 Ac 3+ release. Furthermore, it is necessary for the Ac complex to have high stability against transmetalation reactions and transchelation. To determine the kinetic inertness, 225 Ac(macropa)] 225 was challenged with La, as macropa has a high affinity for this metal ion. A 50-fold excess of La + with respect to the ligand concentration was added to a solution (0.59 μM) radiolabeled with 3+ Ac of macropa at RT. Over 7 days, 3+ 98% of the 225 Ac complex remained unchanged as determined by radio-TLC, indicating that a large molar equivalent of La 225 was unable to replace 3+ Ac 225 Ac 3+ . The stability of 225 Ac(macropa)] + in human serum was also evaluated by radio-TLC, revealing that 225 Ac 3+ remained bound to macropa for at least 8 days.

[0291] 225 Ac(macropa)] + Evaluation of the in vivo distribution of the complex 225 Ac(macropa)] + in vivo stability was determined by its in vivo distribution, 225 Ac(NO3)3 and​​225 Ac(DOTA)] - was tested by comparing its biodistribution. C57BL / 6 mice were injected with 10 - 50 kBq of each radiometal complex via the tail vein and sacrificed at 15 min, 1 h, or 5 h later. The amount of 225 Ac retained in each organ was quantified by gamma counting and reported as the percentage of injected dose per gram of tissue (%ID / g). The results of these tests are summarized in Tables 1 - 3. The inappropriate stability of the 225 Ac complex that results in the loss of the radioisotope in vivo was revealed by the 225 accumulation of [11,12,32] Ac in the mouse liver, spleen, and bone. 225 In Figure 2A, slow blood clearance and excretion are demonstrated in connection with the large accumulation of unbound 225 Ac(NO3)3 in the liver and spleen. + The biodistribution profile of 225 Ac(macropa)] 225 Ac(macropa)] + is clearly different from the biodistribution profile of 225 Ac(NO3)3 (Figure 3B). + Ac(macropa)] 225 Ac(macropa)] + was rapidly removed from the mice, and very little activity was measured in the blood at each hour after injection. Most of the injected dose was excreted in the kidneys and subsequently detected in the urine, as observed in the mice at 15 min and 1 h after injection. 225 Ac(macropa)] 3+ demonstrates moderate kidney and bladder uptake. Importantly, 225 Ac(macropa)] - did not accumulate in any organ over the course of the test, indicating that the complex does not release free 225 Ac 3+ in vivo. Its biodistribution profile is similar to that of [7]

[0292] 225 Ac(macropa)] + Synthesis and Characterization of TAT Conjugates 225 Ac(macropa)] + Due to the inherent stability of the conjugate, macropa was incorporated into the tumor targeting construct. To facilitate its conjugation, a reactive isothiocyanate functional group was installed on one of the picolinate arms of macropa to obtain the novel bifunctional ligand macropa-NCS (Scheme 1). As exemplified by the above reference, macropa-NCS was synthesized over eight steps and characterized by conventional techniques. For one tumor targeting construct, macropa-NCS was conjugated to trastuzumab (Tmab), an FDA-approved monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2) in breast cancer and other cancers.

[33] By virtue of its several-week biological half-life [34,35] , Tmab is an ideal vector for shuttling long-lived 225 Ac radionuclides to tumor cells. 225 Ac-macropa-Tmab showed excellent stability in human serum at 37 °C; after 7 days, >99% of the conjugate remained unchanged (Table 4). Collectively, these results demonstrate the effect of macropa as a chelator for 225 Ac in antibody constructs and other cancer-targeted constructs.

[0293] References 7. M. R. McDevitt, D. Ma, L. T. Lai, J. Simon, P. Borchardt, R. K. Frank, K. Wu, V. Pellegrini, M. J. Curcio, M. Miederer, et al., Science 2001, 294, 1537. ​​11. I. A. Davis, K. A. Glowienka, R. A. Boll, K. A. Deal, M. W. Brechbiel, M. Stabin, P. N. Bochsler, S. Mirzadeh, S. J. Kennel, Nucl. Med. Biol. 1999, 26, 581. 12. K. A. Deal, I. A. Davis, S. Mirzadeh, S. J. Kennel, M. W. Brechbiel, J. Med. Chem. 1999, 42, 2988. 24. A. Roca-Sabio, M. Mato-Iglesias, D. Esteban-Gomez, E. Toth, A. de Blas, C. Platas-Iglesias, T. Rodriguez-Blas, J. Am. Chem. Soc. 2009, 131, 3331. 25. R. Ferreiros-Martinez, D. Esteban-Gomez, E. Toth, A. de Blas, C. Platas-Iglesias, T. Rodriguez-Blas, Inorg. Chem. 2011, 50, 3772. 26. M. P. Jensen, R. Chiarizia, I. A. Shkrob, J. S. Ulicki, B. D. Spindler, D. J. Murphy, M. Hossain, A. Roca-Sabio, C. Platas-Iglesias, A. de Blas, et al., Inorg. Chem. 2014, 53, 6003. 27. A. E. Martell, R. M. Smith, Critical Stability Constants: Vol. 1, Plenum Press, New York; London, 1974. 29. M. G. Ferrier, E. R. Batista, J. M. Berg, E. R. Birnbaum, J. N. Cross, J. W. Engle, H. S. La Pierre, S. A. Kozimor, J. S. Lezama Pacheco, B. W. Stein, et al., Nat. Commun. 2016, 7, 12312. 30. M. G. Ferrier, B. W. Stein, E. R. Batista, J. M. Berg, E. R. Birnbaum, J. W. Engle, K. D. John, S. A. Kozimor, J. S. Lezama Pacheco, L. N. Redman, ACS Cent. Sci. 2017, 3, 176. 32. G. J. Beyer, R. Bergmann, K. Schomacker, F. Rosch, G. Schafer, E. V Kulikov, A. F. Novgorodov, Isot. Isot. Environ. Heal. Stud. 1990, 26, 111. 33. M. M. Moasser, Oncogene2007, 26, 6469. 34. B. Leyland-Jones, K. Gelmon, J.-P. Ayoub, A. Arnold, S. Verma, R. Dias, P. Ghahramani, J. Clin. Oncol. 2003, 21, 3965. 35. D. Leveque, L. Gigou, J. P. Bergerat, Curr. Clin. Pharmacol. 2008, 3, 51. 37. A. P. Kozikowski, F. Nan, P. Conti, J. Zhang, E. Ramadan, T. Bzdega, B. Wroblewska, J. H. Neale, S. Pshenichkin, J. T. Wroblewski, J. Med. Chem. 2001, 44, 298. 38. K. P. Maresca, S. M. Hillier, F. J. Femia, D. Keith, C. Barone, J. L. Joyal, C. N. Zimmerman, A. P. Kozikowski, J. A. Barrett, W. C. Eckelman, et al., J. Med. Chem. 2009, 52, 347. 39. S. M. Hillier, K. P. Maresca, F. J. Femia, J. C. Marquis, C. A. Foss, N. Nguyen, C. N. Zimmerman, J. A. Barrett, W. C. Eckelman, M. G. Pomper, et al., Cancer Res. 2009, 69, 6932. 40. J. A. Barrett, R. E. Coleman, S. J. Goldsmith, S. Vallabhajosula, N. A. Petry, S. Cho, T. Armor, J. B. Stubbs, K. P. Maresca, M. G. Stabin, et al., J. Nucl. Med. 2013, 54, 380. 41. J. Kelly, A. Amor-Coarasa, A. Nikolopoulou, D. Kim, C. Williams Jr., S. Ponnala, J. W. Babich, Eur. J. Nucl. Med. Mol. Imaging 2017, 44, 647. 42. A. Ghosh, W. D. W. Heston, J. Cell. Biochem. 2004, 91, 528. 43. M. S. Dennis, M. Zhang, Y. Gloria Meng, M. Kadkhodayan, D. Kirchhofer, D. Combs, L. A. Damico, J. Biol. Chem. 2002, 277, 35035. 44. C. E. Dumelin, S. Trussel, F. Buller, E. Trachsel, F. Bootz, Y. Zhang, L. Mannocci, S. C. Beck, M. Drumea-Mirancea, M. W. Seeliger, et al., Angew. Chem. Int. Ed. 2008, 47, 3196. 102. M. Mato-Iglesias, A. Roca-Sabio, Z. Palinkas, D. Esteban-Gomez, C. Platas-Iglesias, E. Toth, A. de Blas, T. Rodriguez-Blas, Inorg. Chem. 2008, 47, 7840-7851. 103. A. Roca-Sabio, M. Mato-Iglesias, D. Esteban-Gomez, E. Toth, A. de Blas, C. Platas-Iglesias, T. Rodriguez-Blas, J. Am. Chem. Soc. 2009, 131, 3331-3341. 104. V. J. Gatto, G. W. Gokel, J. Am. Chem. Soc. 1984, 106, 8240-8244. 105. E. R. Neil, M. A. Fox, R. Pal, L.-O. Palsson, B. A. O’Sullivan, D. Parker, Dalton Trans. 2015, 44, 14937-14951. 106. Z. E. A. Chamas, X. Guo, J.-L. Canet, A. Gautier, D. Boyer, R. Mahiou, Dalton Trans. 2010, 39, 7091-7097. 108. D. T. Corson, C. F. Meares, Bioconjug. Chem. 2000, 11, 292-299. 109. G. M. Sheldrick, Acta Crystallogr. Sect. A 2015, 71, 3-8. 110. G. M. Sheldrick, Acta Crystallogr. Sect. A 2008, 64, 112-122. 111. P. Muller, Crystallogr. Rev. 2009, 15, 57-83. 112. O. V Dolomanov, L. J. Bourhis, R. J. Gildea, J. A. K. Howard, H. Puschmann, J. Appl. Crystallogr.2009, 42, 339-341. 113. J. Dilling, R. Krucken, L. Merminga, Eds., ISAC and ARIEL: The TRIUMF Radioactive Beam Facilities and the Scientific Program, Springer, Dordrecht, Netherlands, 2014. 114. J. R. Crawford, P. Kunz, H. Yang, P. Schaffer, T. J. Ruth, Appl. Radiat. Isot. 2017, 122, 222-228. 115. B. Zielinska, C. Apostolidis, F. Bruchertseifer, A. Morgenstern, Solvent Extr. Ion Exch. 2007, 25, 339-349. 116. V. Radchenko, J. W. Engle, J. J. Wilson, J. R. Maassen, F. M. Nortier, W. A. Taylor, E. R. Birnbaum, L. A. Hudston, K. D. John, M. E. Fassbender, J. Chromatogr. A 2015, 1380, 55-63. 117. M. P. Miranda-Hernandez, E. R. Valle-Gonzalez, D. Ferreira-Gomez, N. O. Perez, L. F. Flores-Ortiz, E. Medina-Rivero, Anal. Bioanal. Chem. 2016, 408, 1523-1530. 118. E. W. Price, K. J. Edwards, K. E. Carnazza, S. D. Carlin, B. M. Zeglis, M. J. Adam, C. Orvig, J. S. Lewis, Nucl. Med. Biol. 2016, 43, 566-576. 119. J. Kelly, A. Amor-Coarasa, A. Nikolopoulou, D. Kim, C. Williams, S. Ponnala, J. W. Babich, Eur. J. Nucl. Med. Mol. Imaging 2017, 44, 647-661.

[0294] Some embodiments have been illustrated and described, and those skilled in the art can make modifications, equivalent substitutions, and other types of changes to the compounds of the present technology or their salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers or racemic mixtures described herein after reading the foregoing specification. Each of the foregoing aspects and embodiments can also include or incorporate such modified methods or aspects disclosed with respect to any or all of the other aspects and embodiments.

[0295] The present technology is not limited to the specific embodiments described herein, which are intended as single illustrations of individual aspects of the present technology. Many modifications and variations of the present technology can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Within the scope of the present technology, functionally equivalent methods are apparent to those skilled in the art from the foregoing description in addition to those listed herein. Such modifications and variations are intended to fall within the scope of the appended claims. It is to be understood that the present technology is not limited to a particular method, reagent, compound, composition, labeled compound or biological system, which may of course vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Accordingly, it is intended that the present specification be considered exemplary only, as defined by the scope, range and spirit of the appended claims, the definitions herein and any equivalents thereof.

[0296] The embodiments illustratively described herein can be suitably practiced in the absence of any one or more elements, one or more limitations not disclosed in detail herein. Thus, for example, terms such as "comprising", "including", "containing", etc. are to be read broadly and not limited thereto. Further, the terms and expressions used herein are for purposes of illustration and not of limitation, and are not intended in the use of such terms and expressions to exclude any equivalents of the features shown and described or portions thereof, although it is recognized that various modifications are possible within the scope of the claimed technology. Further, the phrase "consisting essentially of" is understood to include additional elements that do not materially affect the basic and novel characteristics of the elements recited in detail and the claimed technology. The phrase "consisting of" excludes any element not specified.

[0297] Furthermore, when a feature or aspect of the present disclosure is described in terms of a Markush group, one of ordinary skill in the art will recognize that the present disclosure thereby also describes any individual member or subgroup of members of the Markush group. Each of the groupings of the more specific species and subgenera belonging to the general disclosure also forms part of the present invention. This includes the general description of the present invention and is specifically enumerated herein, whether by conditional or negative limitations excluding any subject from its genus, regardless of whether the material is cut off.

[0298] As will be understood by one of ordinary skill in the art, for any and all purposes, particularly in regard to showing a written description, all ranges disclosed herein also include any and all possible subranges and combinations of those subranges. Any recited range can be readily recognized as being sufficiently described and capable of being divided into at least one-half, one-third, one-fourth, one-fifth, one-tenth, etc. of the same range. By way of non-limiting example, each range discussed herein can be readily divided into a lower one-third, middle one-third, and upper one-third, etc. As will also be understood by one of ordinary skill in the art, all language, such as "up to," "at least," "greater than," "less than," etc., includes the recited number and then ranges that can be divided into subranges as discussed above. Finally, as will be understood by one of ordinary skill in the art, ranges include each individual member.

[0299] All publications, patent applications, issued patents, and other documents (e.g., academic journals, papers, and / or textbooks) referred to herein are incorporated herein by reference as if each individual patent publication, patent application, issued patent, or other document were specifically and individually indicated to be incorporated by reference in its entirety. Definitions contained in the text incorporated by reference are excluded to the extent they are inconsistent with the definitions in the present disclosure.

[0300] This technology can include, but is not limited to, the features and combinations of features recited in the following lettered paragraphs, and it is understood that the following paragraphs are not to be construed as being limited within the scope of the appended claims or that all such features need not necessarily be included in such claims. A. Formula I

[0301] [Chemical Formula] [In the formula, Z 1 is H or -X 1 -W 2 and Z 2 is OH or NH-W 3 and Z 3 is H or W 7 and; α is 0 or 1; X 1 is O, NH, or S; W 2 and W 3 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2) w -R’ (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH2CH2-(OCH2CH2) x -OR’ (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may optionally be halo, -N3, -OR’, -CH2CH2-(OCH2CH2) y -R’ (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH2CH2-(OCH2CH2) z-OR' (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -S(O)R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NH2, -N=C=N-R', -SO2Cl, -C(O)Cl, or may be substituted with one or more epoxy groups; W 5 and W 7 are each independently OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2) w -R' (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH2CH2-(OCH2CH2) x -OR' (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may optionally be halo, -N3, -OR', -CH2CH2-(OCH2CH2)y x -R' (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH2CH2-(OCH2CH2) z -OR' (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -S(O)R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NH2, -N=C=N-R', -SO2Cl, -C(O)Cl, or may be substituted with one or more epoxy groups; R' is, each occurrence independently, H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C 10A compound that is cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl, or a pharmaceutically acceptable salt thereof. B. Formula III

[0302]

Chemical formula

[0303]

Chemical formula

[0304]

Chemical formula

[0305]

Chemical formula

[0306]

Chemical formula

[0307]

Chemical formula

[0308]

Chemical formula

[0309]

Chemical formula

[0310]

Chemical Formula

[0311]

Chemical formula

[0312]

Chem.

[0313]

Chem.

[0314] [Chemical formula] [wherein, M 2 is an α-emitting radionuclide], a compound of, or a pharmaceutically acceptable salt thereof, a targeting compound of any one of paragraphs S to U. W. M 2 is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149 ( 149Tb 3+ )、 fermium-255( 255 Fm 3+ )、 thorium-227( 227 Th 4+ )、 thorium-226( 226 Th 4+ )、 astatine-211( 211 At + )、 astatine-217( 217 At + )、 or uranium-230, the targeting compound of paragraph V. X. The targeting compound of formula II is of formula VIII

[0315]

Chemical formula

[0316] [Chem.] [wherein, M 4 is a compound of an α-ray-emitting radionuclide, or a pharmaceutically acceptable salt thereof, which is a target-directed compound of any one of paragraphs S to U. AA. M 4 is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), or uranium-230, which is a target-directed compound of paragraph Z. AB. The target-directed compound of formula II is of formula XIV

[0317] [Chem.] [wherein, M 5 is a compound of an α-ray-emitting radionuclide, or a pharmaceutically acceptable salt thereof, which is a target-directed compound of any one of paragraphs S to U. AC. M 5 is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+) Bismuth-213 213 Bi 3+ ) Lead-212 212 Pb 2+ and / or 212 Pb 4+ ) Terbium-149 149 Tb 3+ ) Fermium-255 255 Fm 3+ ) Thorium-227 227 Th 4+ ) Thorium-226 226 Th 4+ ) Astatine-211 211 At + ) Astatine-217 217 At + ) or Uranium-230, a target-directed compound of Paragraph AB. AD. Formula I

[0318]

Chemical formula

[0319]

Chemical formula

[0320]

Chemical formula

[0321]

Chem.

[0322]

Chem.

[0323]

Chem.

[0324]

Chem.

[0325] [Chemical formula] [wherein, M 2 is an alpha - emitting radionuclide], or a pharmaceutically acceptable salt thereof, and is a modified antibody, modified antibody fragment, or modified binding peptide of any one of paragraphs AM - AQ. AS. M 2 is actinium - 225 ( 225 Ac 3+ ), radium - 223 ( 233 Ra 2+ ), bismuth - 213 ( 213 Bi 3+) lead-212( 212 Pb 2+ and / or 212 Pb 4+ ) terbium-149( 149 Tb 3+ ) fermium-255( 255 Fm 3+ ) thorium-227( 227 Th 4+ ) thorium-226( 226 Th 4+ ) astatine-211( 211 At + ) astatine-217( 217 At + ) or uranium-230, a modified antibody, modified antibody fragment, or modified binding peptide of paragraph AR. AT. The binding may be a thiocyanate bond; the thiocyanate bond results from the conjugation of the compound to an antibody, antibody fragment, or binding peptide; the compound is

[0326]

Chem.

[0327]

Chemical formula

[0328] [Chemistry] [wherein, M 4 is a compound of an α-ray-emitting radionuclide, or a pharmaceutically acceptable salt thereof, a modified antibody, a modified antibody fragment, or a modified binding peptide of any one of paragraphs AM to AQ. AY. M 4 is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), or uranium-230, a modified antibody, a modified antibody fragment, or a modified binding peptide of paragraph AX. AZ. The compound of formula IA is of formula XIII

[0329] [Chemistry] [wherein, M 5 is a compound of an α-ray-emitting radionuclide, or a pharmaceutically acceptable salt thereof, a modified antibody, a modified antibody fragment, or a modified binding peptide of any one of paragraphs AM to AQ. BA. M 5 is actinium-225 ( 225 Ac3+ )、radium-223( 233 Ra 2+ )、bismuth-213( 213 Bi 3+ )、lead-212( 212 Pb 2+ and / or 212 Pb 4+ )、terbium-149( 149 Tb 3+ )、fermium-255( 255 Fm 3+ )、thorium-227( 227 Th 4+ )、thorium-226( 226 Th 4+ )、astatine-211( 211 At + )、astatine-217( 217 At + )、or uranium-230, a modified antibody, modified antibody fragment, or modified binding peptide of paragraph AZ. BB. A composition comprising a pharmaceutically acceptable carrier and a compound of any one of paragraphs A to R. BC. A composition comprising a pharmaceutically acceptable carrier and a targeting compound of any one of paragraphs S to AC, or a composition comprising a pharmaceutically acceptable carrier and a modified antibody, modified antibody fragment, or modified binding peptide of any one of paragraphs AD to BA. BD. A pharmaceutical composition useful for targeted radiotherapy of cancer and / or mammalian tissues overexpressing prostate-specific membrane antigen (「PSMA」) in a subject, comprising a pharmaceutically acceptable carrier and a compound of any one of paragraphs S to AC, or a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a modified antibody, modified antibody fragment, or modified binding peptide of any one of paragraphs AD to BA. BE. The pharmaceutical composition of paragraph BD, comprising an effective amount of a compound for treating cancer and / or mammalian tissues overexpressing PSMA, or an effective amount of a modified antibody, modified antibody fragment, or modified binding peptide for treating cancer and / or mammalian tissues overexpressing PSMA. BF. A pharmaceutical composition according to paragraph BD or BE, wherein the subject has a problem with mammalian tissue expressing somatostatin receptor, bombesin receptor, separase, or a combination of any two or more thereof, and / or mammalian tissue overexpressing PSMA. BG. A pharmaceutical composition according to any one of paragraphs BD to BF, wherein the subject has a problem with one or more of tumors producing growth hormone, neuroendocrine tumors, pituitary tumors, vasoactive intestinal peptide-secreting tumors, small cell lung cancer, gastric cancer, pancreatic cancer, neuroblastoma. BH. A pharmaceutical composition according to any one of paragraphs BD to BG, wherein the subject has a problem with one or more of glioma, breast cancer, adrenal cortical cancer, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer. BI. A pharmaceutical composition according to any one of paragraphs BD to BH, formulated for intravenous administration and optionally containing sterile water, Ringer's solution, or isotonic saline. BJ. A pharmaceutical composition according to any one of paragraphs BD to BI, wherein the effective amount of the compound is about 0.01 μg to about 10 mg of the compound per gram of the pharmaceutical composition. BK. A pharmaceutical composition according to any one of paragraphs BD to BJ, provided in an injectable dosage form. BL. A method of treating a subject, comprising the step of administering to the subject a targeting compound according to any one of paragraphs S to AC, or a modified antibody, modified antibody fragment, or modified binding peptide according to any one of paragraphs AD to BA. BM. A method according to paragraph BL, wherein the subject has a problem with cancer and / or mammalian tissue overexpressing prostate-specific membrane antigen ("PSMA"). BN. A method according to paragraph BM, comprising the step of administering an effective amount of a compound for treating cancer and / or mammalian tissue overexpressing PSMA, or an effective amount of a modified antibody, modified antibody fragment, or modified binding peptide for treating cancer and / or mammalian tissue overexpressing PSMA. BO. Any one of the methods of paragraphs BL - BN, when administered to a subject, where the subject has a problem with mammalian tissue that expresses somatostatin receptors, bombesin receptors, separase, or any combination of two or more thereof, and / or mammalian tissue that overexpresses prostate - specific membrane antigen (「PSMA」). BP. Any one of the methods of paragraphs BL - BO, where the mammalian tissue includes one or more of tumors that produce growth hormone, neuroendocrine tumors, pituitary tumors, vasoactive intestinal peptide - secreting tumors, small - cell lung cancer, gastric cancer, pancreatic cancer, neuroblastoma, and metastatic cancer. BQ. Any one of the methods of paragraphs BL - BP, where the subject has a problem with one or more of glioma, breast cancer, adrenal cortical cancer, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, non - small - cell lung cancer, small - cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell cancer, and prostate cancer. BR. Any one of the methods of paragraphs BL - BQ, where the administering step includes parenteral administration. BS. Any one of the methods of paragraphs BL - BR, where the administering step includes intravenous administration. BT. Any one of the methods of paragraphs BL - BS, where the effective amount is about 0.1 μg to about 50 μg per kilogram of the subject's body weight. BU. A compound comprising a first domain having a blood - protein - binding moiety with low specific affinity for blood proteins, a second domain having a tumor - target - targeting moiety with high affinity for tumor antigens, and a third domain having a chelator. BV. The compound of paragraph BU, where the tumor antigen is PSMA, bombesin, somatostatin receptor, or separase. BW. The blood - protein - binding moiety has a specific affinity for albumin of about 0.5 - 50×10 -6 M, and the tumor - target - targeting moiety has a specific affinity for tumor antigens of about 0.5 - 50×10 -9 M. The compound of paragraph BU or paragraph BV. BX. The following structure

[0330] [Chemical] a compound represented by or a pharmaceutically acceptable salt thereof. BY. 213 Bi 3+ , 211 At + , 225 Ac 3+ , 152 Dy 3+ , 212 Bi 3+ , 211 Bi 3+ , 217 At + , 227 Th 4+ , 226 Th 4+ , 233 Ra 2+ , 212 Pb 2+ or 212 Pb 4+ a composition comprising a compound of paragraph BX that chelates. BZ. A method of treating a subject, the method comprising administering the composition of paragraph BY to the subject. CA. The method of paragraph BZ, wherein the subject has a problem with cancer and / or mammalian tissue that overexpresses prostate-specific membrane antigen ("PSMA"). CB. The method of paragraph CA, comprising administering an effective amount of the composition to treat cancer and / or mammalian tissue that overexpresses PSMA. CC. The method according to any one of paragraphs BZ to CB, wherein the subject has a problem with mammalian tissue that overexpresses prostate-specific membrane antigen ("PSMA"). CD. The method according to any one of paragraphs BZ to CC, wherein the mammalian tissue comprises one or more of a tumor that produces growth hormone, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell lung cancer, a gastric cancer, a pancreatic cancer, a neuroblastoma, and a metastatic cancer. CE. A method according to any one of paragraphs BZ to CD, wherein the subject has one or more problems of glioma, breast cancer, adrenocortical cancer, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell carcinoma, and prostate cancer. CF. A method according to any one of paragraphs BZ to CE, wherein the administering step comprises parenteral administration. CG. A method according to any one of paragraphs BZ to CF, wherein the administering step comprises intravenous administration. CH. A method according to any one of paragraphs BZ to CG, wherein the effective amount is about 0.1 μg to about 50 μg per kilogram of the subject's body weight.

[0331] Other embodiments are described in the following claims, along with the full scope of equivalents to which such claims are entitled. (Appendix) [Appendix 1] Formula I [Chemical Formula 1] JPEG0007699542000139.jpg4970[wherein, Z 1 is H or -X 1 -W 2 and Z 2 is OH or NH-W 3 and Z 3 is H or W 7 ; α is 0 or 1; X 1 is O, NH, or S; W 2 and W 3 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2) w -R' (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH2CH2-(OCH2CH2) x-OR’ (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may, in some cases, be halo, -N3, -OR’, -CH2CH2-(OCH2CH2) y -R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH2CH2-(OCH2CH2) z -OR’ (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or may be substituted with one or more of epoxy groups; W 5 and W 7 are each independently OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2) w -R’ (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH2CH2-(OCH2CH2) x -OR’ (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may, in some cases, be halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y x -R’ (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH2CH2-(OCH2CH2) z-OR' (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -S(O)R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NH2, -N=C=N-R', -SO2Cl, -C(O)Cl, or may be substituted with one or more of epoxy groups; R' is, independently for each occurrence, H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C 10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl], or a pharmaceutically acceptable salt thereof. [Appendix 2] Formula III [Chemical Formula 2] The compound of JPEG0007699542000140.jpg4089, or a pharmaceutically acceptable salt thereof, the compound described in Appendix 1. [Appendix 3] [Chemical Formula 3] The compound of JPEG0007699542000141.jpg4883 or a pharmaceutically acceptable salt thereof, the compound described in Appendix 1 or Appendix 2. [Appendix 4] The compound of Formula I is a compound of Formula VI [Chemical Formula 4] The compound of JPEG0007699542000142.jpg4473, or a pharmaceutically acceptable salt thereof, the compound described in Appendix 1. [Appendix 5] The compound of Formula I is a compound of Formula IX [Chemical Formula 5] The compound of JPEG0007699542000143.jpg4273, or a pharmaceutically acceptable salt thereof, the compound described in Appendix 1. [Appendix 6] The compound of Formula I is a compound of Formula XII [Chemical Formula 6] The compound of JPEG0007699542000144.jpg4775, or a pharmaceutically acceptable salt thereof, which is the compound described in Appendix 1. [Appendix 7] Formula IA [Chemical Formula 7] JPEG0007699542000145.jpg4974[In the formula, M 1 is an α-emitting radionuclide; Z 1 is H or -X 1 -W 2 and Z 2 is OH or NH-W 3 and Z 3 is H or W 7 and α is 0 or 1; X 1 is O, NH, or S; W 2 and W 3 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2) w -R' (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH2CH2-(OCH2CH2) x -OR' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may optionally be halo, -N3, -OR', -CH2CH2-(OCH2CH2) y -R' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH2CH2-(OCH2CH2) z-OR' (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -S(O)R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NH2, -N=C=N-R', -SO2Cl, -C(O)Cl, or may be substituted with one or more epoxy groups; W 5 and W 7 are each independently OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2) w -R' (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH2CH2-(OCH2CH2) x -OR' (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may optionally be halo, -N3, -OR', -CH2CH2-(OCH2CH2)y x -R' (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH2CH2-(OCH2CH2) z -OR' (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -S(O)R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NH2, -N=C=N-R', -SO2Cl, -C(O)Cl, or may be substituted with one or more epoxy groups; R' is, each occurrence independently, H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C 10A compound that is cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl, or a pharmaceutically acceptable salt thereof. [Appendix 8] M 1 is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), or uranium-230, the compound described in Appendix 7. [Appendix 9] The compound of formula I is of formula IV [Chemical formula 8] JPEG0007699542000146.jpg4190[wherein, M 2 is an alpha-emitting radionuclide], the compound described in Appendix 7 or Appendix 8, or a pharmaceutically acceptable salt thereof. [Appendix 10] M 2 is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149 ( 149Tb 3+ )、 fermium-255( 255 Fm 3+ )、 thorium-227( 227 Th 4+ )、 thorium-226( 226 Th 4+ )、 astatine-211( 211 At + )、 astatine-217( 217 At + )、 or uranium-230, the compound according to Appendix 9. [Appendix 11] [Chemical Formula 9] JPEG0007699542000147.jpg4884 or a pharmaceutically acceptable salt thereof, the compound according to Appendix 9. [Appendix 12] M 2 is actinium-225( 225 Ac 3+ )、 radium-223( 233 Ra 2+ )、 bismuth-213( 213 Bi 3+ )、 lead-212( 212 Pb 2+ and / or 212 Pb 4+ )、 terbium-149( 149 Tb 3+ )、 fermium-255( 255 Fm 3+ )、 thorium-227( 227 Th 4+ )、 thorium-226( 226 Th 4+ )、 astatine-211( 211 At + )、 astatine-217( 217 At + )、 or uranium-230, the compound according to Appendix 11. [Appendix 13] The compound of formula IA is of formula VIII [Chemical Formula 10] JPEG0007699542000148.jpg4474[wherein, M 3is a compound of an α-emitting radionuclide, or a pharmaceutically acceptable salt thereof, a compound described in Appendix 7 or Appendix 8. [Appendix 14] M 3 is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), or uranium-230, a compound described in Appendix 13. [Appendix 15] The compound of formula IA is of formula X [Chemical Formula 11] JPEG0007699542000149.jpg4371[wherein, M 4 is a compound of an α-emitting radionuclide, or a pharmaceutically acceptable salt thereof, a compound described in Appendix 7 or Appendix 8. [Appendix 16] M 4 is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149 ( 149 Tb3+ ) fermium-255 ( 255 Fm 3+ ) thorium-227 ( 227 Th 4+ ) thorium-226 ( 226 Th 4+ ) astatine-211 ( 211 At + ) astatine-217 ( 217 At + ) or uranium-230, the compound described in Appendix 15. [Appendix 17] The compound of formula IA is of formula XIII [Chemical formula 12] JPEG0007699542000150.jpg4876 [where M 5 is an alpha-emitting radionuclide], the compound described in Appendix 7 or Appendix 8, or a pharmaceutically acceptable salt thereof. [Appendix 18] M 5 is actinium-225 ( 225 Ac 3+ ) radium-223 ( 233 Ra 2+ ) bismuth-213 ( 213 Bi 3+ ) lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ) terbium-149 ( 149 Tb 3+ ) fermium-255 ( 255 Fm 3+ ) thorium-227 ( 227 Th 4+ ) thorium-226 ( 226 Th 4+ ) astatine-211 ( 211 At + ) astatine-217 ( 217 At + ) or uranium-230, the compound described in Appendix 17. [Appendix 19] Formula II [Chemical formula 13] JPEG0007699542000151.jpg5672[wherein, M 1 is an alpha-emitting radionuclide; Z 1 is H or -L 3 -R 22 and Z 2 is OH or NH-L 4 -R 24 and Z 3 is H or -L 6 -R 28 and α is 0 or 1; X 1 is O, NH, or S; L 3 L 4 L 5 or L 6 is, each time it appears, independently a bond or a linker group; R 22 R 24 R 26 and R 28 are each independently a targeting compound comprising an antibody, an antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, a binding polypeptide (e.g., a selective target-directed oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase-containing moiety (e.g., an oligonucleotide, a DNA or RNA vector, or an aptamer), or a lectin], or a pharmaceutically acceptable salt thereof. [Appendix 20] M 1 is actinium-225( 225 Ac 3+ ), radium-223( 233 Ra 2+ ), bismuth-213( 213 Bi 3+ ), lead-212( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149( 149 Tb 3+ ), fermium-255( 255Fm 3+ )、 thorium-227( 227 Th 4+ )、 thorium-226( 226 Th 4+ )、 astatine-211( 211 At + )、 astatine-217( 217 At + )、 or uranium-230, the targeting compound described in Appendix 19. [Appendix 21] R 22 、 R 24 、 R 26 、 and R 28 are each independently, belimumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semaprimab, nivolumab, pembrolizumab, orlatumumab, atezolizumab, abelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, glembatumumab, nimotuzumab, catumaxomab, etaracizumab, any antigen-binding fragment thereof, prostate-specific membrane antigen ( "PSMA") -binding peptide, somatostatin receptor agonist, bombesin receptor agonist, sepulase-binding compound, or any binding fragment thereof, the targeting compound described in Appendix 19 or Appendix 20. [Appendix 22] The targeting compound of formula II is of formula V [Chemical formula 14] JPEG0007699542000152.jpg4199[wherein, M 2 is an alpha-emitting radionuclide], or a pharmaceutically acceptable salt thereof, the targeting compound described in any one of Appendices 19 to 21. [Appendix 23] M 2 is actinium-225( 225 Ac 3+ ), radium-223( 233 Ra 2+ ), bismuth-213( 213 Bi 3+ ), lead-212( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149( 149 Tb 3+ ), fermium-255( 255 Fm 3+ ), thorium-227( 227 Th 4+ ), thorium-226( 226 Th 4+ ), astatine-211( 211 At + ), astatine-217( 217 At + ), or uranium-230, the target-directed compound described in Appendix 22. [Appendix 24] The target-directed compound of Formula II is a compound of Formula VIII [Chemical Formula 15] JPEG0007699542000153.jpg4576[wherein, M 3 is an alpha-emitting radionuclide], or a pharmaceutically acceptable salt thereof, the target-directed compound described in any one of Appendices 19 to 21. [Appendix 25] M 3 is actinium-225( 225 Ac 3+ ), radium-223( 233 Ra 2+ ), bismuth-213( 213 Bi 3+ ), lead-212( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149( 149 Tb 3+ ), fermium-255( 255 Fm3+ )、 thorium-227( 227 Th 4+ )、 thorium-226( 226 Th 4+ )、 astatine-211( 211 At + )、 astatine-217( 217 At + )、 or uranium-230, the targeting compound described in Supplementary Note 24. [Supplementary Note 26] The targeting compound of Formula II is of Formula XI [Chemical Formula 16] JPEG0007699542000154.jpg5073[wherein M 4 is an α-emitting radionuclide], the targeting compound described in any one of Supplementary Notes 19 to 21, or a pharmaceutically acceptable salt thereof. [Supplementary Note 27] M 4 is actinium-225( 225 Ac 3+ ), radium-223( 233 Ra 2+ ), bismuth-213( 213 Bi 3+ ), lead-212( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149( 149 Tb 3+ ), fermium-255( 255 Fm 3+ ), thorium-227( 227 Th 4+ ), thorium-226( 226 Th 4+ ), astatine-211( 211 At + ), astatine-217( 217 At + ), or uranium-230, the targeting compound described in Supplementary Note 26. [Supplementary Note 28] The targeting compound of Formula II is of Formula XIV [Chemical Formula 17] JPEG0007699542000155.jpg5476[wherein, M 5 is a compound of an α-emitting radionuclide, or a pharmaceutically acceptable salt thereof, which is a target-directed compound according to any one of Appendices 19 to 21. [Appendix 29] M 5 is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), or uranium-230, which is a target-directed compound according to Appendix 28. [Appendix 30] Formula I [Chemical Formula 18] JPEG0007699542000156.jpg4970[wherein, Z 1 is H or -X 1 -W 2 ; Z 2 is OH or NH-W 3 ; Z 3 is H or W 7 ; α is 0 or 1; X 1 is O, NH, or S; W 2 and W 3is, independently of each other, H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2) w -R’ (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH2CH2-(OCH2CH2) x -OR’ (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2) y -R’ (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH2CH2-(OCH2CH2) z -OR’ (wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR’, -OC(O)R’, -C(O)OR’, -C(S)OR’, -S(O)R’, -SO2R’, -SO2(OR’), -SO2NR’2, -P(O)(OR’)2, -P(O)R’(OR’), -P(O)R’2, -CN, -OCN, -SCN, -NCO, -NCS, -NR’-NH2, -N=C=N-R’, -SO2Cl, -C(O)Cl, or an epoxide group; W 5 and W 7 are, independently of each other, OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2) w -R’ (wherein w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH2CH2-(OCH2CH2) x -OR’ (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may optionally be substituted with one or more of halo, -N3, -OR’, -CH2CH2-(OCH2CH2)y x -R’ (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH2CH2-(OCH2CH2) z-OR' (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -S(O)R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NH2, -N=C=N-R', -SO2Cl, -C(O)Cl, or may be substituted with one or more of epoxy groups; R' is, each occurrence independently, H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C 10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl], a compound, or a pharmaceutically acceptable salt thereof, an antibody, antibody fragment, or a conjugate resulting from conjugation to a binding peptide, a modified antibody, modified antibody fragment, or modified binding peptide comprising a bond. [Appendix 31] An antibody is pembrolizumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, obinutuzumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semipramab, nivolumab, pembrolizumab, orlatumumab, atezolizumab, abelumab, durvalumab, capromab pendetide, erlotinib, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, glembatumumab, nimotuzumab, catumaxomab, or etaracizumab, a modified antibody, modified antibody fragment, or modified binding peptide described in Appendix 30. [Appendix 32] The modified antibody, modified antibody fragment, or modified binding peptide according to Appendix 30 or Appendix 31, comprising an antigen-binding fragment of an antibody such as belimumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, ofatumumab, ofatumumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, sirukumab, semaprimab, nivolumab, pembrolizumab, orlaratumab, atezolizumab, abelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, siltuximab, glembatumumab, nimotuzumab, catumaxomab, or etaracizumab. [Appendix 33] The modified antibody, modified antibody fragment, or modified binding peptide according to any one of Appendices 30 to 32, wherein the binding peptide comprises a prostate-specific membrane antigen ( "PSMA") binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a septalase binding compound, or a binding fragment thereof. [Appendix 34] The compound of formula I is a compound of formula III [Chemical formula 19] The modified antibody, modified antibody fragment, or modified binding peptide according to any one of Appendices 30 to 33, which is the compound of JPEG0007699542000157.jpg4089 or a pharmaceutically acceptable salt thereof. [Appendix 35] The binding may be a thiocyanate bond; the thiocyanate bond results from the conjugation of the compound to an antibody, antibody fragment, or binding peptide; the compound is [Chemical formula 20] JPEG0007699542000158.jpg4883 or a pharmaceutically acceptable salt thereof, a modified antibody, a modified antibody fragment, or a modified binding peptide according to any one of Appendices 30 to 34. [Appendix 36] The compound of Formula I is of Formula VI [Chemical Formula 21] JPEG0007699542000159.jpg4473 or a pharmaceutically acceptable salt thereof, a modified antibody, a modified antibody fragment, or a modified binding peptide according to any one of Appendices 30 to 33. [Appendix 37] The compound of Formula I is of Formula IX [Chemical Formula 22] JPEG0007699542000160.jpg4273 or a pharmaceutically acceptable salt thereof, a modified antibody, a modified antibody fragment, or a modified binding peptide according to any one of Appendices 30 to 33. [Appendix 38] The compound of Formula I is of Formula XII [Chemical Formula 23] JPEG0007699542000161.jpg4775 or a pharmaceutically acceptable salt thereof, a modified antibody, a modified antibody fragment, or a modified binding peptide according to any one of Appendices 30 to 33. [Appendix 39] Formula IA [Chemical Formula 24] JPEG0007699542000162.jpg4974 [wherein, M 1 is an α-emitting radionuclide; Z 1 is H or -X 1 -W 2 and Z 2 is OH or NH-W 3 and Z 3 is H or W 7 and α is 0 or 1; X 1is O, NH, or S; W 2 and W 3 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2) w -R' (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH2CH2-(OCH2CH2) x -OR' (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may optionally be substituted with one or more of halo, -N3, -OR', -CH2CH2-(OCH2CH2) y -R' (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH2CH2-(OCH2CH2) z -OR' (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -S(O)R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NH2, -N=C=N-R', -SO2Cl, -C(O)Cl, or an epoxide group; W 5 and W 7 are each independently OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH2CH2-(OCH2CH2) w -R' (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH2CH2-(OCH2CH2) x -OR' (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may optionally be substituted with one or more of halo, -N3, -OR', -CH2CH2-(OCH2CH2)y x -R' (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH2CH2-(OCH2CH2)z -OR' (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -S(O)R', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NH2, -N=C=N-R', -SO2Cl, -C(O)Cl, or may be substituted with one or more of an epoxide group; R' is, each occurrence independently, H, halo, -N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8 cycloalkenyl, C2-C6 alkynyl, C8-C 10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl], a compound, or a pharmaceutically acceptable salt thereof, an antibody, antibody fragment, or a conjugate resulting from conjugation to a binding peptide, a modified antibody, modified antibody fragment, or modified binding peptide containing a bond. [Appendix 40] M 1 is actinium-225( 225 Ac 3+ ), radium-223( 233 Ra 2+ ), bismuth-213( 213 Bi 3+ ), lead-212( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149( 149 Tb 3+ ), fermium-255( 255 Fm 3+ ), thorium-227( 227 Th 4+ ), thorium-226( 226 Th 4+ ), astatine-211( 211 At + ), astatine-217( 217 At +) or uranium-230, the modified antibody, modified antibody fragment, or modified binding peptide described in Appendix 39. [Appendix 41] The antibody is pembrolizumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, ofatumumab, ocaratuzumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, siltuximab, semipramab, nivolumab, pembrolizumab, orlatumumab, atezolizumab, abelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, cixutumumab, glembatumumab, nimotuzumab, catumaxomab, or etaracizumab, the modified antibody, modified antibody fragment, or modified binding peptide described in Appendix 39 or Appendix 40. [Appendix 42] The antibody fragment is the antigen-binding fragment of pembrolizumab, mogamulizumab, blinatumomab, ibritumomab tiuxetan, ofatumumab, ocaratuzumab, rituximab, inotuzumab ozogamicin, moxetumomab pasudotox, brentuximab vedotin, daratumumab, ipilimumab, cetuximab, necitumumab, panitumumab, dinutuximab, pertuzumab, trastuzumab, trastuzumab emtansine, siltuximab, semipramab, nivolumab, pembrolizumab, orlatumumab, atezolizumab, abelumab, durvalumab, capromab pendetide, elotuzumab, denosumab, Ziv-aflibercept, bevacizumab, ramucirumab, tositumomab, gemtuzumab ozogamicin, alemtuzumab, cixutumumab, glembatumumab, nimotuzumab, catumaxomab, or etaracizumab, the modified antibody, modified antibody fragment, or modified binding peptide described in any one of Appendices 39 to 41. [Appendix 43] The modified antibody, modified antibody fragment, or modified binding peptide according to any one of Appendices 39 to 42, wherein the binding peptide comprises a prostate-specific membrane antigen ("PSMA") binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a separase-binding compound, or a binding fragment thereof. [Appendix 44] The compound of formula I is a compound of formula IV [Chemical Formula 25] JPEG0007699542000163.jpg4190[wherein M 2 is an α-emitting radionuclide], or a pharmaceutically acceptable salt thereof, being the modified antibody, modified antibody fragment, or modified binding peptide according to any one of Appendices 39 to 43. [Appendix 45] M 2 is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), or uranium-230, being the modified antibody, modified antibody fragment, or modified binding peptide according to Appendix 44. [Appendix 46] The bond may be a thiocyanate bond; the thiocyanate bond results from the conjugation of the compound to an antibody, antibody fragment, or binding peptide; the compound is [Chemical formula 26] the modified antibody, modified antibody fragment, or modified binding peptide according to Supplementary Note 44, which is [Supplementary Note 47] M 2 is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), or uranium-230, which is the modified antibody, modified antibody fragment, or modified binding peptide according to Supplementary Note 46. [Supplementary Note 48] The compound of formula IA is a compound of formula VIII [Chemical formula 27] JPEG0007699542000165.jpg4474 [wherein M 3 is an alpha-emitting radionuclide], or a pharmaceutically acceptable salt thereof, which is the modified antibody, modified antibody fragment, or modified binding peptide according to any one of Supplementary Notes 39 to 43. [Supplementary Note 49] M 3is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), or uranium-230, the modified antibody, modified antibody fragment, or modified binding peptide described in Supplementary Note 48. [Supplementary Note 50] The compound of formula IA is a compound of formula X [Formula 28] JPEG0007699542000166.jpg4371[wherein M 4 is an α-emitting radionuclide], or a pharmaceutically acceptable salt thereof, the modified antibody, modified antibody fragment, or modified binding peptide described in any one of Supplementary Notes 39 to 43. [Supplementary Note 51] M 4 is actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and / or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 (255 Fm 3+ )、 thorium-227( 227 Th 4+ )、 thorium-226( 226 Th 4+ )、 astatine-211( 211 At + )、 astatine-217( 217 At + )、 or uranium-230, the modified antibody, modified antibody fragment, or modified binding peptide described in Supplementary Note 50. [Supplementary Note 52] The compound of Formula IA is of Formula XIII [Chemical Formula 29] JPEG0007699542000167.jpg4876[wherein, M 5 is an α-emitting radionuclide], the modified antibody, modified antibody fragment, or modified binding peptide described in any one of Supplementary Notes 39 to 43, or a pharmaceutically acceptable salt thereof. [Supplementary Note 53] M 5 is actinium-225( 225 Ac 3+ )、 radium-223( 233 Ra 2+ )、 bismuth-213( 213 Bi 3+ )、 lead-212( 212 Pb 2+ and / or 212 Pb 4+ )、 terbium-149( 149 Tb 3+ )、 fermium-255( 255 Fm 3+ )、 thorium-227( 227 Th 4+ )、 thorium-226( 226 Th 4+ )、 astatine-211( 211 At + )、 astatine-217( 217 At + )、 or uranium-230, the modified antibody, modified antibody fragment, or modified binding peptide described in Supplementary Note 52. [Appendix 54] A composition comprising a pharmaceutically acceptable carrier and a compound described in any one of Appendices 1 to 18. [Appendix 55] A composition comprising a pharmaceutically acceptable carrier and a target-directed compound described in any one of Appendices 19 to 29, or a composition comprising a pharmaceutically acceptable carrier and a modified antibody, modified antibody fragment, or modified binding peptide described in any one of Appendices 30 to 53. [Appendix 56] A pharmaceutical composition useful for targeted radiotherapy of cancer and / or mammalian tissues overexpressing prostate-specific membrane antigen ("PSMA") in a subject, comprising a pharmaceutically acceptable carrier and a compound described in any one of Appendices 19 to 29, or a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a modified antibody, modified antibody fragment, or modified binding peptide described in any one of Appendices 30 to 53. [Appendix 57] The pharmaceutical composition according to Appendix 56, comprising an effective amount of a compound for treating cancer and / or mammalian tissues overexpressing PSMA, or an effective amount of a modified antibody, modified antibody fragment, or modified binding peptide for treating cancer and / or mammalian tissues overexpressing PSMA. [Appendix 58] The pharmaceutical composition according to Appendix 56 or Appendix 57, wherein the subject has problems with mammalian tissues expressing somatostatin receptor, bombesin receptor, separase, or any combination of two or more thereof, and / or mammalian tissues overexpressing PSMA. [Appendix 59] The pharmaceutical composition according to any one of Appendices 56 to 58, wherein the subject has one or more problems with a tumor producing growth hormone, neuroendocrine tumor, pituitary tumor, vasoactive intestinal peptide-secreting tumor, small cell lung cancer, gastric cancer, pancreatic cancer, or neuroblastoma. [Appendix 60] The pharmaceutical composition according to any one of Appendices 56 to 59, wherein the subject has one or more problems of glioma, breast cancer, adrenocortical cancer, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell cancer, and prostate cancer. [Appendix 61] The pharmaceutical composition according to any one of Appendices 56 to 60, which is formulated for intravenous administration and optionally contains sterile water, Ringer's solution, or isotonic saline. [Appendix 62] The pharmaceutical composition according to any one of Appendices 57 to 61, wherein the effective amount of the compound is about 0.01 μg to about 10 mg of the compound per gram of the pharmaceutical composition. [Appendix 63] The pharmaceutical composition according to any one of Appendices 56 to 62, which is provided in an injectable dosage form. [Appendix 64] A method for treating a subject, comprising administering to the subject a targeting compound according to any one of Appendices 19 to 29, or administering a modified antibody, modified antibody fragment, or modified binding peptide according to any one of Appendices 30 to 53. [Appendix 65] The method according to Appendix 64, wherein the subject has a problem of cancer and / or mammalian tissue that overexpresses prostate-specific membrane antigen ("PSMA"). [Appendix 66] The method according to Appendix 65, comprising administering an effective amount of a compound for treating cancer and / or mammalian tissue that overexpresses PSMA, or an effective amount of a modified antibody, modified antibody fragment, or modified binding peptide for treating cancer and / or mammalian tissue that overexpresses PSMA. [Appendix 67] The method according to any one of Appendices 64 to 66, wherein the subject has a problem of mammalian tissue that expresses somatostatin receptor, bombesin receptor, separase, or any combination of two or more thereof, and / or mammalian tissue that overexpresses prostate-specific membrane antigen ("PSMA"). [Appendix 68] The method according to any one of Appendices 64 to 67, wherein the mammalian tissue comprises one or more of a tumor producing growth hormone, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide secreting tumor, small cell lung cancer, gastric cancer, pancreatic cancer, neuroblastoma, and metastatic cancer. [Appendix 69] The method according to any one of Appendices 64 to 68, wherein the subject has one or more problems of glioma, breast cancer, adrenocortical cancer, cervical cancer, vulvar cancer, endometrial cancer, primary ovarian cancer, metastatic ovarian cancer, non-small cell lung cancer, small cell lung cancer, bladder cancer, colon cancer, primary gastric adenocarcinoma, primary colorectal adenocarcinoma, renal cell cancer, and prostate cancer. [Appendix 70] The method according to any one of Appendices 64 to 69, wherein the administering step comprises parenteral administration. [Appendix 71] The method according to any one of Appendices 64 to 70, wherein the administering step comprises intravenous administration. [Appendix 72] The method according to any one of Appendices 66 to 71, wherein the effective amount is about 0.1 μg to about 50 μg per kilogram of the subject's body weight. [Appendix 73] A compound comprising a first domain having a blood protein binding moiety with low specific affinity for blood proteins, a second domain having a tumor targeting moiety with high affinity for tumor antigens, and a third domain having a chelator. [Appendix 74] The compound according to Appendix 73, wherein the tumor antigen is PSMA, bombesin, somatostatin receptor, or separase. [Appendix 75] The blood protein binding moiety has a specific affinity for albumin of about 0.5 to 50×10 -6 M, and the tumor targeting moiety has a specific affinity for tumor antigens of about 0.5 to 50×10 -9 M. The compound according to Appendix 73. [Appendix 76] The following structure [Formula 30] The compound represented by JPEG0007699542000168.jpg79155, or a pharmaceutically acceptable salt thereof. [Appendix 77] 213 Bi 3+ , 211 At + , 225 Ac 3+ , 152 Dy 3+ , 212 Bi 3+ , 211 Bi 3+ , 217 At + , 227 Th 4+ , 226 Th 4+ , 233 Ra 2+ , 212 Pb 2+ , or 212 Pb 4+ A composition comprising the compound according to Appendix 76 that chelates

Claims

1. Formula III 【Chemical 1】 [wherein, X １ is O, NH, or S; W ２ is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH ２ CH ２ -(OCH ２ CH ２ ) ｗ -R' (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH ２ CH ２ -(OCH ２ CH ２ ) ｘ -OR' (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may optionally be halo, -N ３ , -OR', -CH ２ CH ２ -(OCH ２ CH ２ ) ｙ -R' (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH ２ CH ２ -(OCH ２ CH ２ ) ｚ -OR' (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -S(O)R', -SO ２ R', -SO ２ (OR'), -SO ２ NR' ２ , -P(O)(OR') ２ , -P(O)R'(OR'), -P(O)R' ２ , -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NH ２ , -N = C = N-R', -SO ２ Cl, -C(O)Cl, or substituted with one or more of an epoxide group; R’ is, independently for each occurrence, H, halo, -N ３ , C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, C ２ ~C ６ alkenyl, C ５ ~C ８ cycloalkenyl, C ２ ~C ６ alkynyl, C ８ ~C １０ cycloalkynyl, C ５ ~C ６ aryl, heterocyclyl, or heteroaryl], or a pharmaceutically acceptable salt thereof.

2. The following formula: [Chemical Formula 2] a compound of or a pharmaceutically acceptable salt thereof.

3. Formula IV 【Chemical Formula 3】 [wherein, M ２ is an α-ray-emitting radionuclide; X １ is O, NH, or S; W ２ is alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH ２ CH ２ -(OCH ２ CH ２ ) ｗ -R' (where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), or -CH ２ CH ２ -(OCH ２ CH ２ ) ｘ -OR' (where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), and each of them may optionally be halo, -N ３ , -OR', -CH ２ CH ２ -(OCH ２ CH ２ ) ｙ -R' (where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -CH ２ CH ２ -(OCH ２ CH ２ ) ｚ -OR' (where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -S(O)R', -SO ２ R', -SO ２ (OR'), -SO ２ NR' ２ , -P(O)(OR') ２ , -P(O)R'(OR'), -P(O)R' ２ , -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NH ２ , -N=C=N-R', -SO ２ Cl, -C(O)Cl, or substituted with one or more of an epoxide group; R' is, independently for each occurrence, H, halo, -N ３ , C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, C ２ ~C ６ alkenyl, C ５ ~C ８ cycloalkenyl, C ２ ~C ６ alkynyl, C ８ ~C １０ cycloalkynyl, C ５ ~C ６ aryl, heterocyclyl, or heteroaryl], or a pharmaceutically acceptable salt thereof.

4. M ２ is actinium-225 ( ２２５ Ac ３＋ ), radium-223 ( ２３３ Ra ２＋ ), bismuth-213 ( ２１３ Bi ３＋ ), lead-212 ( ２１２ Pb ２＋ and / or ２１２ Pb ４＋ ), terbium-149 ( １４９ Tb ３＋ ), fermium-255 ( ２５５ Fm ３＋ ), thorium-227 ( ２２７ Th ４＋ ), thorium-226 ( ２２６ Th ４＋ ), astatine-211 ( ２１１ At ＋ ), astatine-217 ( ２１７ At ＋ ), or uranium-230, the compound according to claim 3.

5. The following formula: 【Chemical Formula 4】 a compound of or a pharmaceutically acceptable salt thereof, wherein M2 is actinium-225 (225Ac3+), radium-223 (233Ra2+), bismuth-213 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine-217 (217At+), or uranium-230; a compound of or a pharmaceutically acceptable salt thereof.

6. A composition comprising a pharmaceutically acceptable carrier and a compound according to any one of Claims 1 to 5.

7. The following structure 【Chemical Formula 5】 a compound represented thereby, or a pharmaceutically acceptable salt thereof.

8. ２１３ Bi ３＋ , ２１１ At ＋ , ２２５ Ac ３＋ , １５２ Dy ３＋ , ２１２ Bi ３＋ , ２１１ Bi ３＋ , ２１７ At ＋ , ２２７ Th ４＋ , ２２６ Th ４＋ , ２３３ Ra ２＋ , ２１２ Pb ２＋ , or ２１２ Pb ４＋ A composition comprising the compound according to claim 7, which chelates

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