Macrocyclic complexes of alpha-emitting radionuclides and their use in targeted radiotherapy of cancer.

Abstract

This technology provides compounds and compounds that: The following formula [Formula 1] wherein M is an alpha-emitting radionuclide. or a pharmaceutically acceptable salt thereof, useful for treating cancer. [Selection diagram] None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 478,945, filed March 30, 2017, the entire disclosure of which is incorporated herein by reference for any and all purposes.

[0002] U.S. Government License Rights This invention was made with Government support under Grant No. UL1TR00457 awarded by the National Institutes of Health. The United States Government has certain rights in this invention. [Background technology]

[0003] The present technology relates generally to macrocyclic complexes of alpha-emitting radionuclides, as well as compositions comprising such compounds and methods of use. Summary of the Invention

[0004] In one embodiment, the composition of formula I is

[0005] [ka] [wherein M is an α-emitting radionuclide, A 1 is a nitrogen atom (N) or CR 1 A 2 is a nitrogen atom (N) or CR 2 A 3 is a nitrogen atom (N) or CR 3 A 4 is a nitrogen atom (N) or CR 4 A 5 is a nitrogen atom (N) or CR 5 A 6 is a nitrogen atom (N) or CR 6 A 7 is a nitrogen atom (N) or CR 7 A 8is a nitrogen atom (N) or CR 8 A 9 is a nitrogen atom (N) or CR 9 A 10 is a nitrogen atom (N) or CR 10 where A represents 1 , A 2 , A 3 , A 4 , and A 5 Up to three of A may be nitrogen atoms. 6 , A 7 , A 8 , A 9 , and A 10 up to three of R may be nitrogen atoms; 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, halo, -OR', -(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCHCH) y -OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', -S are each independently selected from O2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and an epoxide group, and optionally halo, -(OCH2CH2) x -R', -(OCH2CH2) y-OR', -OR', -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR 'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SO2R', -SO 2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and the epoxide group is -(CH2) n - each independently linked to the carbon atom to which it is attached by a linker (wherein n is 1, 2, or 3); or directly adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 one or two pairs of groups are interconnected to form a 5- to 6-membered substituted or unsubstituted carbocyclic or nitrogen-containing ring; R' at each occurrence is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl, C2-C6 alkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl, or two R' groups attached to the same atom are interconnected to form a 3- to 6-membered ring] or a pharma- ceutically acceptable salt thereof.

[0006] L in formula (I) 1 and L 2 The group is -(CH2) p -, and p is a value of 1, 2, or 3. The subscripts r and s in formula (I) are independently 0 or 1. When r is 0 or s is 0, then L 1 or L 2 are each absent, thereby resulting in a direct bond between the respective aromatic ring and the macrocycle.

[0007] In one aspect, a targeting composition is provided that is represented by formula (II):

[0008] [ka]

[0009] In formula (II), A 1 ~A 10 , M, L 1 , L 2 , r, and s are R 1 ~R 10 have the same meaning as provided for any embodiment herein, except that at least one of is or includes a selective cancer cell targeting group.

[0010] In another aspect, a method of producing a composition according to Formula (I) and / or Formula (II) is provided.

[0011] In other aspects, the present technology also provides compositions (e.g., pharmaceutical compositions) and medicaments comprising any one of the embodiments of a compound of formula II (or a pharma- ceutically acceptable salt thereof) disclosed herein and a pharma- ceutically acceptable carrier or one or more excipients or fillers.

[0012] In another aspect, the technology provides a method of treating cancer by administering an effective amount of a targeting composition according to formula (II) to a subject having cancer. [Brief description of the drawings]

[0013] [Figure 1A] Figure 1A shows the X-ray crystal structure of [La(Hmacropa)(HO)]·(ClO) (Figure 1A, side view). Ellipsoids are drawn at the 50% probability level. Counteranions and hydrogen atoms attached to carbon are omitted for clarity. [Figure 1B]Figure 1B shows the X-ray crystal structure of [La(Hmacropa)(HO)]·(ClO) (Figure 1B, top view). Ellipses are drawn at the 50% probability level. The counteranion and hydrogen atoms attached to the carbon are omitted for clarity. [Figure 1C] Figure 1C shows the X-ray crystal structure of [Lu(macropa)]·ClO4·DMF (side view). Ellipsoids are drawn at the 50% probability level. Counteranions and hydrogen atoms attached to carbons are omitted for clarity. [Figure 1D] Figure 1D shows the X-ray crystal structure of [Lu(macropa)]·ClO4·DMF (Figure 1D, top view). Ellipses are drawn at the 50% probability level. Counteranions and hydrogen atoms attached to carbon are omitted for clarity. [Figure 2A] FIG. 2A shows the biodistribution of Ac(NO) to select organs after intravenous injection in mice. Adult C57BL / 6 mice were sacrificed 15 min, 1 h, or 5 h after injection. Values ​​for each time point are shown as the mean %ID / g ± 1 SD. [Figure 2B] Figure 2B shows the biodistribution of [225Ac(macropa)]+ (Figure 2B) to select organs after intravenous injection in mice. Adult C57BL / 6 mice were sacrificed 15 min, 1 h, or 5 h after injection. Values ​​for each time point are shown as the mean %ID / g ± 1SD. [Figure 2C] Figure 2C shows the biodistribution of [225Ac(DOTA)]- (Figure 2C) to select organs after intravenous injection in mice. Adult C57BL / 6 mice were sacrificed 15 min, 1 h, or 5 h after injection. Values ​​for each time point are shown as the mean %ID / g ± 1SD. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] The following terms are used throughout as defined below:

[0015] As used herein and in the appended claims, the singular articles, e.g., "a" and "an" and "the" and similar referents in connection with describing these elements (particularly in connection with the following claims), should be construed to include the singular and plural, unless otherwise indicated herein or clearly contradicted by context. The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, 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 otherwise clearly contradicted by context. 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 pose limitations in the claims, unless otherwise indicated. No language in this specification should be construed as indicating any non-claimed element in its nature.

[0016] As used herein, "about" is understood by those of ordinary skill in the art and will vary to some extent depending on the context in which it is used. If there are uses of the term that are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term.

[0017] In general, a reference to an element, e.g., 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, radioisotopes, e.g., tritium, C 14 , P 32 and S 35 Compounds containing the same 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 skill in the art based on the disclosure herein.

[0018] In general, "substituted" refers to an organic group (e.g., an alkyl group) as defined below, in which one or more bonds to a hydrogen atom contained therein are replaced by a single bond to a non-hydrogen or non-carbon atom. Substituents also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds to a heteroatom. 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 halogens (i.e., F, Cl, Br, and I); hydroxyl; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyl (oxo); carboxylates; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; pentafluorosulfanyl (i.e., SF5), sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; nitriles (i.e., CN); and the like.

[0019] 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.

[0020] As used herein, C m ~C n For example, C1~C 12, C1-C8, or C1-C6, when used before a group, refers to the group containing m to n carbon atoms.

[0021] Alkyl groups include straight-chain and branched-chain alkyl groups having 1 to 12 carbon atoms, typically 1 to 10 carbons or, in some embodiments, 1 to 8, 1 to 6, or 1 to 4 carbon atoms. Examples of straight-chain alkyl groups include groups such as, for example, 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. Alkyl groups can be substituted or unsubstituted. Representative substituted alkyl groups can be substituted one or more times with substituents, such as those described above, including, but not limited to, haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.

[0022] Cycloalkyl groups include 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, cycloalkyl groups have 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, and the like. Cycloalkyl groups may be substituted or unsubstituted. Substituted cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. However, substituted cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups can be mono- or more than mono-substituted, such as, but not limited to, 2,2-, 2,3-, 2,4-2,5- or 2,6-disubstituted cyclohexyl groups, which can be substituted with substituents such as those described above.

[0023] Cycloalkylalkyl groups are alkyl groups as defined above, in which the hydrogen or carbon bond of the alkyl group is replaced by a single bond to the cycloalkyl group as defined above.In some embodiments, the cycloalkylalkyl group has 4 to 16 carbon atoms, 4 to 12 carbon atoms, and usually has 4 to 10 carbon atoms.Cycloalkylalkyl groups can be substituted or unsubstituted.Substituted cycloalkylalkyl groups can be substituted in the alkyl, cycloalkyl, or alkyl and cycloalkyl portions of the group.Representative substituted cycloalkylalkyl groups can be mono-substituted or more than once, for example, mono-substituted, di-substituted, or tri-substituted with substituents such as, but not limited to, those described above.

[0024] Alkenyl groups include straight and branched chain alkyl groups as defined above, except that at least one double bond is present between two carbon atoms. Alkenyl groups have 2 to 12 carbon atoms, and typically have 2 to 10 carbons or, in some embodiments, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, alkenyl groups have 1, 2, or 3 carbon-carbon double bonds. Examples include, but are not limited to, vinyl, allyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(CH2CH3)=CH2, among others. Alkenyl groups may be substituted or unsubstituted. Representative substituted alkenyl groups may be mono-substituted or more than one time substituted, for example, mono-substituted, di-substituted, or tri-substituted with substituents such as, but not limited to, those listed above.

[0025] Cycloalkenyl groups include cycloalkyl groups as defined above that have at least one double bond between two carbon atoms. Cycloalkenyl groups can be substituted or unsubstituted. In some embodiments, cycloalkenyl groups can have one, two or three double bonds, but do not contain aromatic compounds. Cycloalkenyl groups have 4 to 14 carbon atoms, or in some embodiments, 5 to 14 carbon atoms, 5 to 10 carbon atoms, or even 5, 6, 7, or 8 carbon atoms. Examples of cycloalkenyl groups include cyclohexenyl, cyclopentenyl, cyclohexadienyl, cyclobutadienyl, and cyclopentadienyl.

[0026] Cycloalkenylalkyl groups are alkyl groups as defined above, in which the hydrogen or carbon bond of the alkyl group is replaced by a single bond to a cycloalkenyl group as defined above.Cycloalkenylalkyl groups can be substituted or unsubstituted.Substituted cycloalkenylalkyl groups can be substituted with alkyl, cycloalkenyl or the alkyl and cycloalkenyl portions of the group.Representative substituted cycloalkenylalkyl groups can be substituted one or more times with substituents such as those described above.

[0027] Alkynyl groups include straight and branched chain alkyl groups as defined above, except that at least one triple bond is present between two carbon atoms. Alkynyl groups have 2 to 12 carbon atoms, typically 2 to 10 carbons or, in some embodiments, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, alkynyl groups have one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to, -C≡CH, -C≡CCH3, -CH2C≡CCH3, -C≡CCH2CH(CH2CH3)2, among others. Alkynyl groups may be substituted or unsubstituted. Representative substituted alkynyl groups may be mono-substituted or more than one time substituted, for example, mono-substituted, di-substituted, or tri-substituted with substituents such as, but not limited to, those listed above.

[0028] 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, aryl groups contain 6 to 14 carbons in these ring portions, and in others, 6 to 12, and even 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphthyl. Aryl groups can be substituted or unsubstituted. The phrase "aryl group" includes groups that contain fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). Representative substituted aryl groups can be mono-substituted or more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, optionally substituted with substituents such as those described above.

[0029] An aralkyl group is an alkyl group as defined above, in which 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 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. The aralkyl group may be substituted or unsubstituted. Substituted aralkyl groups may be substituted at the alkyl, aryl, or alkyl and aryl portions of the group. 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.

[0030] 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, such as, but not limited to, N, O, and S. In some embodiments, heterocyclyl groups contain 1, 2, 3, or 4 heteroatoms. In some embodiments, heterocyclyl groups include mono-, bi-, and tricyclic rings having 3 to 16 ring members, with other such groups having 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. Heterocyclyl groups encompass aromatic, partially unsaturated, and saturated ring systems, such as imidazolyl, imidazolinyl, and imidazolidinyl groups. The term "heterocyclyl group" includes those containing fused aromatic and non-aromatic groups, such as fused ring species including benzotriazolyl, 2,3-dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl. The phrase includes bridged polycyclic ring systems containing heteroatoms, such as, but not limited to, quinuclidyl, etc. Heterocyclyl groups can be substituted or unsubstituted.Heterocyclyl 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, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, Benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, synthonyl These include linyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl, tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl, tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups.Representative substituted heterocyclyl groups may be mono-substituted or more than mono-substituted, for example, but not limited to, pyridyl or morpholinyl groups that are 2-, 3-, 4-, 5-, or 6-substituted, or di-substituted with various substituents, such as those listed above.

[0031] Heteroaryl groups are aromatic ring compounds containing five or more ring members, one or more of which is a heteroatom, such as, but not limited to, 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 in which all rings are aromatic, such as indolyl groups, and in which only one of the rings is aromatic, such as 2,3-dihydroindolyl groups. Heteroaryl groups can be substituted or unsubstituted. Thus, the phrase "heteroaryl group" includes fused ring compounds as well as 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 a variety of substituents, such as those described above.

[0032] Heterocyclylalkyl groups are alkyl groups as defined above, where the hydrogen or carbon bond of the alkyl group is replaced by a single bond to a heterocyclyl group as defined above. Heterocyclylalkyl groups may be substituted or unsubstituted. Substituted heterocyclylalkyl groups may be substituted at the alkyl, heterocyclyl or alkyl and heterocyclyl portions 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.

[0033] Heteroaralkyl groups are alkyl groups as defined above, in which the hydrogen or carbon bond of the alkyl group is replaced by a single bond to a heteroaryl group as defined above.Heteroaralkyl groups can be substituted or unsubstituted.Substituted heteroaralkyl groups can be substituted at the alkyl, heteroaryl or alkyl and heteroaryl portions of the group.Representative substituted heteroaralkyl groups can be substituted one or more times with substituents such as those described above.

[0034] Groups described herein that have more than one point of attachment (i.e., divalent, trivalent, or polyvalent) in the compounds of the present technology are named by using 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 so on. Substituents that have a single point of attachment to the compounds of the present technology are not applied using the nomenclature of "ene". Thus, for example, chloroethyl is not referred to herein as chloroethylene. Such groups may be substituted or unsubstituted.

[0035] 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 straight-chain alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groups include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those described above.

[0036] As used herein, the terms "alkanoyl" and "alkanoyloxy" can refer to -C(O)-alkyl and -OC(O)-alkyl groups, respectively, and in some embodiments, the alkanoyl or alkanoyloxy groups each contain 2 to 5 carbon atoms. Similarly, the terms "aryloyl" and "aryloyloxy" refer to -C(O)-aryl and -OC(O)-aryl groups, respectively.

[0037] The terms "aryloxy" and "arylalkoxy" refer to a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to an oxygen atom at 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.

[0038] As used herein, the term "carboxylic acid" refers to a compound having a -C(O)OH group. As used herein, the term "carboxylate" refers to a compound having a -C(O)O -"Protected carboxylate" refers to -C(O)OG, where G is a carboxylate protecting group. Carboxylate protecting groups are well known to those skilled in the art. An extensive list of protecting groups for carboxylate functional groups can be found in Protective Groups in Organic Synthesis, Greene, TW; Wuts, PGM, John Wiley & Sons, New York, NY, (3rd Edition, 1999), which can be added or removed using the procedures described therein, which is incorporated herein by reference in its entirety and for all purposes as if fully set forth herein.

[0039] As used herein, the term "ester" refers to an ester of -COOR 70 R 70 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group, as defined herein.

[0040] The term “amide” (or “amido”) includes C- and N-amide groups, i.e., —C(O)NR, respectively. 71 R 72 , and -NR 71 C(O)R 72 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. Amide groups thus include, but are not limited to, carbamoyl groups (-C(O)NH2) and formamide groups (-NHC(O)H). In some embodiments, an amide is -NR 71 C(O)-(C 1~5In some cases the amide is -NHC(O)-alkyl, and the group is termed "carbonylamino"; in others the amide is -NHC(O)-alkyl, and the group is termed "alkanoylamino".

[0041] As used herein, the term "nitrile" or "cyano" refers to a --CN group.

[0042] The urethane groups include N- and O-urethane groups, i.e., -NR 73 C(O)OR 74 and -OC(O)NR 73 R 74 R 73 and R 74 R is independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein. 73 can also be H.

[0043] As used herein, the term "amine" (or "amino") refers to -NR 75 R 76 The 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.

[0044] The term "sulfonamide" includes S- and N-sulfonamide groups, i.e., -SONR, respectively. 78 R 79 and -NR 78 SO2R 79R 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. Thus, sulfonamide groups include, but are not limited to, sulfamoyl groups (-SO2NH2). In some embodiments herein, the sulfonamide is -NHSO2-alkyl, and is referred to as an "alkylsulfonylamino" group.

[0045] The term "thiol" refers to the -SH group and the sulfide to the -SR group. 80 groups, and sulfoxides include -S(O)R 81 groups, and sulfones include -SOR 82 groups, sulfonyl includes -SOOR 83 Contains: 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.

[0046] The term "urea" refers to -NR 84 -C(O)-NR 85 R 86 R 84 , R 85 , and R 86 The groups are independently hydrogen or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group, as defined herein.

[0047] The term "amidine" refers to -C(NR 87 )NR 88 R 89 and -NR 87 C(NR88 )R 89 [In the formula, 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.

[0048] The term "guanidine" refers to -NR 90 C(NR 91 )NR 92 R 93 [In the formula, 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.

[0049] The term "enamine" refers to a -C(R 94 )=C(R 95 )NR 96 R 97 and -NR 94 C(R 95 )=C(R 96 )R 97 [In the formula, R 94 , R 95 , R 96 and R 97 are each independently hydrogen, a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl, or heterocyclylalkyl group, as defined herein.

[0050] 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.

[0051] As used herein, the term "hydroxyl" refers to either -OH or its ionized form, -O - It can mean:

[0052] The term "imide" refers to -C(O)NR 98 C(O)R 99 , [where 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.

[0053] The term "imine" refers to -CR 100 (NR 101 ) and -N(CR 100 R 101 ) group [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, with the proviso that R 100 and R 101 means that neither is hydrogen at the same time.

[0054] As used herein, the term "nitro" refers to the group --NO.

[0055] As used herein, the term "trifluoromethyl" means --CF.sub.3.

[0056] As used herein, the term "trifluoromethoxy" means --OCF.

[0057] The term "azido" refers to --N3.

[0058] The term "trialkylammonium" refers to the -N(alkyl) group. Trialkylammonium groups carry a positive charge and therefore usually have an associated anion, such as a halogen anion.

[0059] The term "trifluoromethyl diaziride" means

[0060] [ka] means...

[0061] The term "isocyano" means --NC.

[0062] The term "isothiocyano" refers to --NCS.

[0063] The term "pentafluorosulfanyl" means -SF5.

[0064] As will be understood by those skilled in the art, for any and all purposes, particularly with respect to providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of those subranges. Any described range is fully described, and one can easily recognize that the same range can be divided into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be easily divided into a lower third, a middle third, and an upper third. As will also be understood by those skilled in the art, all language, such as "up to," "at least," "greater than," "less than," etc., refers to a range that is included in the recited number and can then be divided into the subranges discussed above. Finally, as will be understood by those skilled in the art, a range includes 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 to 5 atoms means a group having 1, 2, 3, 4, or 5 atoms, etc.

[0065] Pharmaceutically acceptable salts of the compounds described herein are within the scope of the present technology and include acid or base addition salts that retain the desired pharmacological activity and are biologically desirable (e.g., the salts are not excessively toxic, allergenic, or irritating and are bioavailable). When the compounds of the present technology have a basic group, such as an amino group, the pharma-ceutically acceptable salts can be formed with inorganic acids (e.g., hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginic acid, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, oxalic acid, tartaric acid, lactic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (e.g., aspartic acid and glutamic acid). When the compounds of the present technology have an acidic group, such as a carboxylic acid group, this can be easily oxidized 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 in situ during the isolation and purification of the compounds or by separately reacting the purified compounds in their free base or free acid form, respectively, with the appropriate acid or base and isolating the salt thus formed.

[0066] Those skilled in the art understand that the compounds of the present technology can show the phenomenon of tautomerism, conformational isomerism, geometric isomerism and / or stereoisomerism.Since the formula drawings in this specification and claims can only represent one of possible tautomeric, conformational isomerism, stereochemical or geometric isomerism forms, it should be understood that the present technology encompasses any tautomeric, conformational isomerism, stereochemical and / or geometric isomerism forms of the compounds having one or more of the utilities described herein, and the mixture of these various different forms.

[0067] "Tautomers" refers to isomeric forms of a compound that are in equilibrium with one another. The presence and concentration of isomeric forms depends on the environment in which the compound is found, and may vary depending, for example, on whether the compound is a solid or in the form of an organic or aqueous solution. For example, in aqueous solution, quinazolinone may exhibit the following isomeric forms, which are referred to as tautomers with one another:

[0068] [ka] . As another example, guanidine can exhibit the following isomeric forms in protic organic solutions, also referred to as tautomers with respect to one another:

[0069] [ka] .

[0070] Because of the limitations to representing compounds by structural formulas, it should be understood that all chemical formulas of compounds described herein represent all tautomeric forms of the compounds and are within the scope of the present technology.

[0071] Stereoisomers of a compound (also known as optical isomers) include all chiral, diastereomeric, and racemic forms of a structure, unless a specific stereochemistry is explicitly indicated.Thus, compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms, as is apparent from the drawing.Both racemic and diastereomeric mixtures, as well as individual optical isomers, can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and all of these stereoisomers are within the scope of the present technology.

[0072] The compounds of the present technology can exist as solvates, particularly hydrates. Hydrates can form during the preparation of the compounds or compositions containing the compounds, or hydrates can form over time due to the hygroscopic nature of the compounds. The compounds of the present technology can also exist as organic solvates, including DMF, ether, and alcohol solvates, among others. The identification and preparation of any particular solvate is within the skill of a person skilled in the art of synthetic organic chemistry or medicinal chemistry.

[0073] Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. Within this disclosure, too, Arabic numerals refer to the referenced citation, the full literature details of which are set forth immediately preceding the claims. The disclosures of these publications, patents and published patent specifications are hereby incorporated by reference into this disclosure in order to more fully describe the present technology.

[0074] This technology Although targeted radiotherapy has been practiced for some time using macrocyclic complexes of radionuclides, currently used macrocycles (e.g., DOTA) generally form complexes with insufficient stability with radionuclides, particularly those of larger size, such as actinium, radium, bismuth, and lead isotopes, etc. Such instability leads to dissociation of the radionuclide from the macrocycle, thereby resulting in a lack of selectivity for the target tissue, which also results in toxicity to non-target tissues.

[0075] The present technology provides new macrocyclic complexes that are substantially more stable than those of the prior art. Thus, these new complexes are substantially less toxic to non-target tissues than the complexes of the art and can advantageously target cancer cells more efficiently. Furthermore, the new complexes can advantageously be formed at room temperature, in contrast to DOTA-type complexes that generally require elevated temperatures (e.g., at least 80°C) for complexation with radionuclides. The present technology also specifically uses alpha-emitting radionuclides instead of beta-emitting radionuclides. Alpha-emitting radionuclides are much more energetic and therefore substantially more potent than beta-emitting radionuclides.

[0076] Thus, in one embodiment, the composition of formula I comprises:

[0077] [ka] wherein M is an alpha-emitting radionuclide, or a pharma- ceutically acceptable salt thereof. Exemplary alpha-emitting radionuclides include, but are not limited to, 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 + ), and uranium-230.

[0078] In formula I, A 1 is a nitrogen atom (N) or CR 1 A 2 is a nitrogen atom (N) or CR 2 A 3 is a nitrogen atom (N) or CR 3 A 4 is a nitrogen atom (N) or CR 4 A 5 is a nitrogen atom (N) or CR 5 A 6 is a nitrogen atom (N) or CR 6 A 7 is a nitrogen atom (N) or CR 7 A 8 is a nitrogen atom (N) or CR 8 A 9 is a nitrogen atom (N) or CR 9 A 10 is a nitrogen atom (N) or CR 10 where A represents 1 , A 2 , A 3 , A 4 , and A 5 Up to three of A may be nitrogen atoms. 6 , A 7 , A 8 , A 9 , and A 10Up to three of R can be nitrogen atoms. Since the A groups are independently selected, the composition can be symmetrical or asymmetrical. In the case of an asymmetrical system, for example, one of the aromatic rings can have only one ring carbon atom and the other aromatic ring can have one, two, or three ring nitrogen atoms, or, for example, one of the aromatic rings can have a single ring nitrogen atom and the other aromatic ring can have two or three ring nitrogen atoms. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 (hereinafter, "R group") is H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, halo, -OR', -(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCHCH) y -OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SO2R', -SO2 are each independently selected from halo, -OR', -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and an epoxide group, and optionally are each independently selected from halo, -OR', -(OCH2CH2) x -R', -(OCH2CH2) y-OR', -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and the epoxide group are -(CH2) n - each independently linked to the carbon atom to which it is attached by a linker, where n is 1, 2, or 3; or directly adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 One or two pairs of groups are interconnected to form a 5-6 membered substituted or unsubstituted carbocyclic or nitrogen-containing ring; R' at each occurrence is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl, C2-C6 alkynyl, C5-C6 aryl, poly(ethylene glycol), heterocyclyl, or heteroaryl, or two R' groups attached to the same atom are interconnected to form a 3-6 membered ring. Heteroatom-containing functional groups (i.e., "functional groups") can function, for example, to modify hydrophilicity or hydrophobicity, act as reactive functional groups (e.g., for binding to cell targeting agents), or participate in complexing with radionuclides. Some examples of functional groups include alkylnyl, halogen atoms (e.g., F, Cl, Br, or I), -OR', -(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCHCH) y-OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', - Included are SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -C(O)R', -C(S)R', -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N3, -N=C=N-R', -SO2Cl, -C(O)Cl, and epoxide groups, or a subset thereof. In any embodiment herein, any one or more of the above functional groups can be excluded or required to be present.

[0079] L in formula (I) 1 and L 2 The group is -(CH2) p - where p is a value of 1, 2, or 3. The subscripts r and s in formula (I) are independently 0 or 1. When r is 0 or s is 0, then L 1 or L 2 are each absent, thereby resulting in a direct bond between the respective aromatic ring and the macrocycle.

[0080] In any embodiment herein, this is R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 and may be at least one of a halogen atom; -OR'; -(OCH2CH2) x -R', where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; -(OCHCH) y-OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR'; -OC(O)R'; -C(O)OR'; -C(S)OR'; -C(O)NR'R'; -C(S)NR'R'; -NR'C(O)R'; -NR'C(S)R'; -NR'R'; -NR'C(O)NR'; -NR'C(S)NR'; -S(O)R'; -SOR'; -SO2R'; -SO2NR'2; -P(O)(OR')2; -P(O)R'(OR'); -P(O)R'2; -NO2; and CN, or a subset thereof (herein referred to as the "first set of functional groups"). In any embodiment herein, this is R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 and a functional group selected from -C(O)R'; -C(S)R'; -OCN; -SCN; -NCO; -NCS; -NR'-NR'R'; -N3; ​​-N=C=N-R'; -SO2Cl; -C(O)Cl; and an epoxide group, or a subset thereof (referred to herein as the "second set of functional groups"). 1 , R 2 , R 3 , R 4 , and R 5 and / or R 6 , R 7 , R 8 , R 9 , and R 10 At least one of R is selected from a first set of functional groups. In any embodiment herein, this is 1 , R 2 , R 3 , R 4 , and R 5 and / or R 6 , R 7 , R 8 , R9 , and R 10 At least one of R is selected from a second set of functional groups. In any embodiment herein, this is 1 , R 2 , R 3 , R 4 , and R 5 and / or R 6 , R 7 , R 8 , R 9 , and R 10 is selected from a first set of functional groups, and 1 , R 2 , R 3 , R 4 , and R 5 At least one of and / or R 6 , R 7 , R 8 , R 9 , and R 10 At least one of is selected from a second set of functional groups.

[0081] A 1 , A 2 , A 3 , A 4 , and A 5 is not a nitrogen atom and / or A 6 , A 7 , A 8 , A 9 , and A 10 It is possible that A is not a nitrogen atom. For example, 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , and A 10 may not be all nitrogen, and the composition may have the formula Ia

[0082] [ka] or a pharma- ceutically acceptable salt thereof.

[0083] In any embodiment herein, A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , and A 10 At least one of A may be a nitrogen atom. 1 , A 2 , A 3 , A 4 , and A 5 At least one of A is a nitrogen atom, 6 , A 7 , A 8 , A 9 , and A 10 At least one of A may be a nitrogen atom. 1 Or A 5 and / or A 6 Or A 10 The following subgeneric structures are subclasses of compositions having a single nitrogen atom in each aromatic ring:

[0084] [ka] or a pharma- ceutically acceptable salt thereof.

[0085] In any embodiment herein, it is possible that any of the above structures take at least one of the indicated R groups as functional groups or, in particular, from a first or second set of functional groups, also referred to herein as "first set functional groups" and "second set functional groups", respectively. For example, in formula (Ib), R 2 , R 3 , R 4 , R 5 , R7 , R 8 , R 9 , and R 10 It is possible that at least one of the R groups shown is not H. In any embodiment herein, any of the above structures may take at least one of the R groups shown as a first set of functional groups and at least one of the R groups shown as a second set of functional groups. For example, in formula (Ib), R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , and R 10 At least one of R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , and R 10 It is possible that at least one of the R groups in one of the aromatic rings and / or at least one of the R groups in the other aromatic ring is a first set functional group. For example, in formula (Ib), R 2 , R 3 , R 4 , and R 5 At least one of and / or R 7 , R 8 , R 9 , and R 10 At least one of the R groups in one of the aromatic rings and / or at least one of the R groups in the other aromatic ring may be a first set functional group. In any embodiment herein, it may be that at least one of the R groups in one of the aromatic rings and / or at least one of the R groups in the other aromatic ring is a second set functional group. For example, in formula (Ib), R 2 , R 3 , R 4 , and R 5 At least one of and / or R 7 , R 8 , R9 , and R 10 At least one of the R groups in one of the aromatic rings and / or at least one of the R groups in the other aromatic rings may be a first set functional group, and at least one of the R groups in one of the aromatic rings and / or at least one of the R groups in the other aromatic rings may be a second set functional group. For example, in formula (Ib), R 2 , R 3 , R 4 , and R 5 At least one of and / or R 7 , R 8 , R 9 , and R 10 may be a first set functional group, and R 2 , R 3 , R 4 , and R 5 At least one of and / or R 7 , R 8 , R 9 , and R 10 At least one of the functional groups may be of a second set.

[0086] In any embodiment herein, at least two of A1, A2, A3, A4, A5, A6, A7, A8, A9, and A10 may be nitrogen atoms. 1 , A 2 , A 3 , A 4 , and A 5 At least two of A are nitrogen atoms, and / or 6 , A 7 , A 8 , A 9 , and A 10 At least two of A may be nitrogen atoms. 1 , A 2 , A 3 , A 4 , and A5 Two of the atoms are nitrogen atoms, and A 6 , A 7 , A 8 , A 9 , and A 10 It is possible that two of the aromatic rings are nitrogen atoms. The following subgeneric structures are exemplary of a subclass of compositions having two nitrogen atoms in each aromatic ring, or a pharma- ceutically acceptable salt thereof:

[0087] [ka] .

[0088] In any embodiment herein of formula (Ie) and (If), R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 , and R 10 It is possible that at least one of the R groups may be either a first set functional group or a second set functional group. In any embodiment herein, this means that any of the above structures may take at least one of the R groups shown as a first set functional group and at least one of the R groups shown as a second set functional group. For example, in formula (Ie), R 2 , R 3 , R 4 , R 7 , R 8 , and R 9 may be a first set functional group, and R 2 , R 3 , R 4 , R 7 , R 8 , and R 9At least one of the R groups in one of the aromatic rings and / or at least one of the R groups in the other aromatic ring may be a first set functional group. For example, in formula (Ie), R 2 , R 3 , and R 4 At least one of and / or R 7 , R 8 , and R 9 At least one of the R groups in one of the aromatic rings and / or at least one of the R groups in the other aromatic ring may be a first set functional group. In any embodiment herein, it may be that at least one of the R groups in one of the aromatic rings and / or at least one of the R groups in the other aromatic ring is a second set functional group. For example, in formula (Ie), R 2 , R 3 , and R 4 At least one of and / or R 7 , R 8 , and R 9 At least one of the R groups in one of the aromatic rings and / or at least one of the R groups in the other aromatic rings may be a second set functional group. In any embodiment herein, this may be the case where at least one of the R groups in one of the aromatic rings and / or at least one of the R groups in the other aromatic rings is a first set functional group, and at least one of the R groups in one of the aromatic rings and / or at least one of the R groups in the other aromatic rings is a second set functional group. For example, in formula (Ie), R 2 , R 3 , and R 4 At least one of and / or R 7 , R 8 , and R 9 may be a first set functional group, and R 2 , R 3 , and R 4 At least one of and / or R 7 , R 8 , and R 9At least one of the functional groups in the second set can be a functional group in the second set. An example of a similar set is shown in the formula (If) as "R 2 , R 3 , and R 4 " An example of "R 2 , R 4 , and R 5 " and "R 7 , R 8 , and R 9 " An example of "R 7 , R 9 , and R 10 " can be provided by replacing

[0089] In any embodiment herein, A in formula (I) 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , and A 10 At least three of A may be nitrogen atoms. 1 , A 2 , A 3 , A 4 , and A 5 At least three of A are nitrogen atoms, and / or 6 , A 7 , A 8 , A 9 , and A 10 At least three of the aromatic rings may be nitrogen atoms. The following subgeneric structures are sub-classes of compositions having three nitrogen atoms in each aromatic ring:

[0090] [ka] or a pharma- ceutically acceptable salt thereof.

[0091] In any embodiment herein of formula (Ig), R 2 , R 4 , R7 , and R 9 At least one of may be a first set functional group or a second set functional group. In any embodiment herein of formula (Ig), R 2 , R 4 , R 7 , and R 9 and may be at least one of the first set functional groups, and at least one R 2 , R 4 , R 7 , and R 9 It is possible that R can be a second set of functional groups. In any embodiment herein of formula (Ig), R 2 and R 4 At least one of and / or R 7 and R 9 In any embodiment herein of formula (Ig), at least one of R 2 and R 4 At least one of and / or R 7 and R 9 In any embodiment herein of formula (Ig), it is possible that at least one of R 2 and R 4 At least one of and / or R 7 and R 9 At least one of R 2 and R 4 At least one of and / or R 7 and R 9 It is possible that at least one of the functional groups is of a second set.

[0092] In any embodiment herein, it may be that at least one of the A groups in at least one of the aromatic rings in formula (I) is a carbon atom having a first set functional group attached thereto as an R group. In any embodiment herein, it may be that at least one of the A groups in each of the aromatic rings is a carbon atom having a first set functional group attached thereto as an R group. For example, in formula (I), (Ia), or (Ib), A 2 and / or A 7 (In other words, A 4 and / or A 9 ) can be a carbon atom having a first set functional group attached thereto. 1 and / or A 6 (In other words, A 5 and / or A 10 In the case where is a carbon atom, the carbon atom may have a first set of functional groups attached thereto. The following subgeneric structures are representative of the compositions described above:

[0093] [ka] JPEG0007675500000012.jpg245165 or some exemplary pharma- ceutically acceptable salt thereof.

[0094] This structure also corresponds to the following exemplary structure:

[0095] [ka] The compound may be asymmetric in its selection of functional groups such as those provided in or a pharma- ceutically acceptable salt thereof.

[0096] In any embodiment herein, it may be that at least one of the A groups in at least one of the aromatic rings in formula (I) is a carbon atom having a second set of functional groups attached thereto as an R group. In any embodiment herein, it may be that at least one of the A groups in each of the aromatic rings is a carbon atom having a second set of functional groups attached thereto as an R group, or that only one of the aromatic rings contains at least one second set of functional groups. In any embodiment herein, the second set of functional groups is specifically A 2 , A 3 , or A 4 to, or A 7 , A 8 Or A 9 More specifically, 3 Or A 8 The following subgeneric structures are representative of the above compositions containing at least one second set of functional groups:

[0097] [ka] JPEG0007675500000015.jpg113160 or some exemplary pharma- ceutically acceptable salts thereof.

[0098] In any embodiment herein, at least one of the R groups in any of the above structures in an aromatic ring can be a first set functional group. In any embodiment herein, the first set functional group can be in the same ring that contains the second set functional group.

[0099] In any embodiment herein, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R10 Of the groups, one or two pairs of immediately adjacent groups are interconnected to form R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 R forms a 4- to 6-membered carbocyclic or nitrogen-containing ring, optionally substituted with one or more groups as indicated above for 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 The interconnection of the groups is A 1 , A 2 , A 3 , A 4 , and A 5 and / or resulting in a fused ring system comprising the ring shown in formula (I) containing A 6 , A 7 , A 8 , A 9 , and A 10 It is possible that this results in a fused ring system comprising the ring shown in formula (I) which comprises:

[0100] In any embodiment herein, it may be said that these structures include at least one fused ring system that includes at least one of the depicted aromatic rings that includes an A group. Exemplary subgenus structures of such structures are as follows:

[0101] [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0102] In formula (Iv), A 1 , A 4 , A 5, A 6 , A 9 , A 10 , L 1 , L 2 , r, s, and M are as indicated in any embodiment herein; R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, halo, -OR', -(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCHCH) y -OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', -SO 2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and an epoxide group, and optionally selected from the group consisting of halo, -OR', -(OCH2CH2) x -R', -(OCH2CH2) y -OR', -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and the epoxide group are -(CH2) n- each occurrence is independently linked to the carbon atom to which it is attached by a linker, where n is 1, 2, or 3; R' is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl, C2-C6 alkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl. In any embodiment herein, R 15 and R 16 The groups can optionally be interconnected to form a second fused ring, which can be the same or different from the first fused ring. In any embodiment herein, R 11 , R 12 , R 13 , and R 14 may not be further interconnected, which leaves the fused rings as a bicyclic fused ring system; however, in any embodiment herein, R 11 , R 12 , R 13 , and R 14 It is possible that two adjacent groups from between can be interconnected, thereby forming a tricyclic fused ring system.

[0103] In any embodiment herein of formula (Iv), R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 At least one of may be a group selected from -C(O)R'; -C(S)R'; -OCN; -SCN; -NCO; -NCS; -NR'-NR'R'; -N3; ​​-N=C=N-R'; -SO2Cl; -C(O)Cl; and an epoxide group. In any embodiment herein of formula (Iv), R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 At least one of the following is a halogen atom; -OR'; -(OCH2CH2) x-R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCHCH) y and -CN.

[0104] In any embodiment herein, it may be said that these structures include two fused ring systems that include each of the depicted aromatic rings that contain an A group. Exemplary subgenus structures of such structures are as follows:

[0105] [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0106] In formula (Iw), A 1 , A 4 , A 5 , A 6 , A 9 , A 10 , L 1 , L 2 , r, s, and M are as defined above, and R 11 , R 12 , R 13 , R 14 , R 17 , R 18 , R 19 , and R 20 are independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, halo, -OR', -(OCH2CH2) x-R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCHCH) y -OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', -SO 2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and an epoxide group, and optionally selected from the group consisting of halo, -OR', -(OCH2CH2) x -R', -(OCH2CH2) y -OR', -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and the epoxide group are -(CH2) n - each occurrence is independently linked to the carbon atom to which it is attached by a linker, where n is 1, 2, or 3; R', at each occurrence, is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl, C2-C6 alkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl.

[0107] In any embodiment herein of formula (Iw), A 1 , A 4 , A 5 , A 6 , A9 , and A 10 At least one of A may be a nitrogen atom. 1 , A 4 , and A 5 At least one (i.e., one, two, or all) of A is a nitrogen atom; 6 , A 9 , and A 10 At least one (i.e., one, two, or all) of the may be a nitrogen atom. Exemplary subgeneric structures of such structures are as follows:

[0108] [ka] or a pharma- ceutically acceptable salt thereof is provided.

[0109] In another aspect, the technology provides a composition useful for targeted radiotherapy of cancer. The composition targets (i.e., selectively binds) to cancer cells by including in its structure a selective cancer cell targeting group that selectively directs the composition to cancer cells. The composition can be conveniently represented by formula (I), except that at least one of the R groups includes a selective cancer cell targeting group. The selective cancer cell targeting group can be any group known in the art that is capable of selectively targeting cancer cells. As an example, the selective cancer cell targeting group can target a receptor site specific to cancer cells. The cancer cell targeting group can be composed of amino acids linked by peptide bonds. The selective cancer cell targeting group of any embodiment herein can include a cancer targeting antibody, an antibody fragment, a selective targeting oligopeptide containing up to 50 amino acids, an enzyme, a nucleobase-containing moiety (e.g., an oligonucleotide, a DNA or RNA vector, or an aptamer), or a lectin. In any of the embodiments herein, any of the aforementioned cancer cell targeting agents can be attached or adsorbed onto a particle (e.g., a nanoparticle or microparticle) with the particle being attached to one of the aromatic rings of the macrocyclic composition by a reactive functional group.

[0110] The targeting composition has the formula (II)

[0111] [ka] It is represented by:

[0112] In formula (II), A 1 ~A 10 , M, L 1 , L 2 , r, and s represent at least one of the R groups (R 1 ~R 10The same meaning is set forth herein for any embodiment, except that R is or comprises a selective cancer cell targeting group, which may be any one or more of the selective cancer cell targeting groups set forth above, including particles containing such groups. In particular, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 At least one of the groups is a selective cancer cell targeting group, or an alkylene, -O-, -S-, -(OCH2CH2) z - (wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -C(O)-, -OC(O)-, -C(O)O-, -C(S)O-, -C(O)NR'-, -C(S)NR', ​​-NR'C(O)-, -NR'C(S)-, -NR'-, -NR'C(O)N-, -NR'C(S)N-, -S(O)-, -SO2-, -S(O)2O-, -SON2NR'-, -P(O)(OR')-, -P(O)(R')-, -C(NR')-, -OC(NR')-, -SC(NR')-, and optionally -O-, -S-, -(OCH2CH2) z -, -C(O)-, -OC(O)-, -C(O)O-, -C(S)O-, -C(O)NR'-, -C(S)NR', ​​-NR'C(O)-, -NR'C(S)-, -NR'-, -NR'C(O)N-, -NR'C(S)N-, -S(O)-, -SO2-, -S(O)2O-, -SON2NR'-, -P(O)(OR')-, -P(O)(R')-, -C(NR')-, -OC(NR')-, -SC(NR')- are each independently linked by a C1-C3 alkylene to the carbon atom to which it is attached. Thus, in formula (II), the R group (R 1 ~R 10A similar series of subgeneric structures under formula (II) includes, in each of these subgeneric formulas, the same number of subgeneric structures under formula (I), except that at least one of the R groups (R 1 ~R 10 (Ia) to (Ix) are derived from the formulae (Ia) to (Ix) by requiring at least one of the following: (Ia) to (Ix) include a selective cancer cell targeting group. Thus, the subgenera of structures under formula (II) can be defined as formulae (II-a) to (II-x) in analogy with formulae (II-a) to (II-x).

[0113] In other aspects, methods of producing compositions according to formula (I) and formula (II) are provided. In such methods, an aromatic ring can be attached to the macrocyclic moiety by methods well known in the art to produce a ligand moiety corresponding to the structure shown in formula (I) or formula (II), except that it does not contain an alpha-emitting radionuclide M. This ligand is then coupled to a radionuclide by methods well known in the art. When an aromatic ring is attached to the macrocyclic moiety, a functional group, e.g., R 1 ~R 10 Any of those provided for in the formula (I) are usually present on an aromatic ring, often in protected form; however, in some cases, the aromatic ring may be protected by R 1 ~R 10The macrocyclic moiety may be attached to the macrocyclic moiety prior to functionalization with any of the functional groups provided for in formula (II). To generate a composition under formula (II), a composition under formula (I) containing at least one reactive functional group is reacted with a selective cancer cell targeting group to attach the selective cancer cell targeting group to the aromatic ring attached to the macrocyclic moiety via the reactive functional group. For example, an isocyanate or isothiocyanate reactive functional group may be included on at least one aromatic ring of the composition in formula (I), and the resulting functionalized composition is added to an amino acid-containing targeting agent by reacting the amino group with the isocyanate or isothiocyanate group in the amino acid-containing targeting agent to generate a targeting composition of formula (II). In this way, the amino-containing targeting agent is attached to the macrocyclic complex by a urea or thiourea bond. Many other modes of attachment with different bonds can be implemented depending on the reactive functional group used. Attachment of the selective cancer cell targeting group can be performed in the unlinked or linked form of formula (I). Significantly, the unconjugated form of formula (I) can be conjugated to a radionuclide in high radiochemical yields, e.g., at least or greater than 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.).

[0114] Because the targeted composition according to formula (II) contains a targeting agent that is attached by reaction of a reactive functional group with the targeting agent, the targeted composition according to formula (II) generally does not substantially contain reactive functional groups, such as those used to attach the targeting agent at a first location. Thus, in any embodiment herein, the targeted composition according to formula (II) does not include any of the functional groups R under formula (I) except that the reactive functional groups are found in a second set of functional groups. 1 ~R 10 The group may include any of the groups described for.

[0115] The present technology also provides compositions (e.g., pharmaceutical compositions) and pharmaceutical products comprising any one of the embodiments of the compound of formula II (or a pharma- ceutically acceptable salt thereof) disclosed herein and a pharma- ceutically acceptable carrier or one or more additives or fillers (collectively referred to as "pharma- ceutically acceptable carriers" unless otherwise specified). The compositions can be used in the methods and treatments described herein. The pharmaceutical compositions can include an effective amount of any one of the embodiments of the compound of the present technology disclosed herein. In any of the above embodiments, the effective amount can be determined for a subject. By "effective amount" is meant the amount of the compound or composition required to produce a desired effect. Non-limiting examples of effective amounts include amounts or doses that produce acceptable toxicity and bioavailability levels for therapeutic (pharmaceutical) use, including, but not limited to, the treatment of, for example, prostate cancer, breast cancer, or bladder cancer. Other examples of effective amounts include amounts or doses that can reduce symptoms associated with, for example, prostate cancer, breast cancer, or bladder cancer, such as reducing the growth and / or metastasis of prostate cancer, breast cancer, or bladder cancer. An effective amount can be about 0.01 μg to about 1 mg of compound per gram of composition, preferably about 0.1 μg to about 500 μg of compound per gram of composition. As used herein, a "subject" or "patient" is a mammal, such as a cat, dog, rodent, or primate. Typically, a subject is a human, preferably a human suffering from or suspected of suffering from non-small cell lung cancer, bladder cancer, or colon cancer (such as colon adenocarcinoma). The terms "subject" and "patient" can be used interchangeably.

[0116] In any of the embodiments of the present technology described herein, the pharmaceutical composition can be packaged in a unit dosage form. The unit dosage form is effective in treating non-small cell lung cancer, bladder cancer, or colon cancer (such as colon adenocarcinoma). In general, the unit dosage form containing the compound of the present technology will vary depending on patient considerations. Such considerations include, for example, age, protocol, condition, sex, extent of disease, contraindications, concomitant therapy, and the like. Exemplary unit dosage forms based on these considerations may also be adjusted or modified by a physician skilled in the art. For example, a unit dosage form for a patient containing the compound of the present technology may be 1×10 -4 g / kg to 1 g / kg, preferably 1×10 -3 The dosage of the compound of the present technology may also vary 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, lozenges, suppositories, patches, nasal sprays, injections, implantable sustained release formulations, mucoadherent films, topical varnishes, lipid complexes, and the like.

[0117] Pharmaceutical compositions can be prepared by mixing one or more compounds of formula II, pharma- ceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof with pharma- ceutically acceptable carriers, additives, binders, excipients, etc., to prevent and treat disorders associated with cancer (e.g., prostate cancer, breast cancer, or bladder cancer). The compounds and compositions described herein can be used to prepare formulations and medicaments for treating, for example, prostate cancer, breast cancer, or bladder cancer. Such compositions can be in the form of, for example, granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions, or solutions. The compositions can be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or by implanted reservoirs. Parenteral or systemic administration includes, but is not limited to, subcutaneous, intravenous, intraperitoneal, and intramuscular injections. The following dosage forms are given by way of example and should not be construed as limiting the instant present technology.

[0118] For oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gel capsules and caplets are acceptable solid dosage forms.These can be prepared, for example, by mixing one or more compounds of the present technology, or their pharma-ceutically acceptable salts or tautomers, 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, arabic gum, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymers or glycerides. In some cases, the oral dosage form may contain other ingredients that aid 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, flavorings, or perfumes. Tablets and pills may be further treated with suitable coating materials known in the art.

[0119] Liquid dosage forms for oral administration can be in the form of pharma- ceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which can contain inert excipients such as water. Pharmaceutical formulations and medicaments can be prepared as liquid suspensions or solutions using sterile liquids, such as, but not limited to, oils, water, alcohol, and combinations thereof. Pharmaceutically suitable surfactants, suspending agents, emulsifying agents can be added for oral or parenteral administration.

[0120] As mentioned above, suspension can contain oil. Such oil includes, but is not limited to, peanut oil, sesame oil, cottonseed oil, corn oil and olive oil. Suspension formulation can also contain ester of fatty acid, such as ethyl oleate, isopropyl myristate, fatty acid glyceride and acetylated fatty acid glyceride. Suspension formulation can contain alcohol, such as, but is not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ether, such as, but is not limited to, poly(ethylene glycol), petroleum hydrocarbon, such as mineral oil and petrolatum; and water can also be used in suspension formulation.

[0121] Injectable dosage forms generally include aqueous suspensions or oily suspensions, which can be prepared using suitable dispersants or wetting agents and suspending agents. Injectable forms may be in solution or suspension phases, and are prepared with solvents or excipients. Acceptable solvents or vehicles include sterile water, Ringer's solution, or isotonic aqueous saline solution. Alternatively, sterile oils can be used as solvents or suspending agents. Usually, oils or fatty acids are non-volatile, including natural or synthetic oils, fatty acids, mono-, di-, or tri-glycerides.

[0122] For injection, the pharmaceutical formulation and / or drug product may be a powder suitable for reconstitution with an appropriate solution as described above. Examples include, but are not limited to, freeze-dried, rotary-dried or spray-dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulation may optionally contain stabilizers, pH adjusters, surfactants, bioavailability modifiers, and combinations thereof.

[0123] 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 aerosols containing any suitable solvent, and optionally other compounds, such as, but not limited to, stabilizers, antibacterial agents, antioxidants, pH adjusters, surfactants, bioavailability adjusters, and combinations thereof.Carriers and stabilizers vary according to the required amount of a particular compound, but usually 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, sugars or sugar alcohols.Aqueous and non-aqueous (e.g., in the form of fluorocarbon propellants) aerosols are usually used for the delivery of the compounds of the present technology by inhalation.

[0124] In addition to these representative dosage forms mentioned above, pharma- ceutically acceptable excipients and carriers are well known to those skilled in the art and are therefore included in the technology of the present invention. Such excipients and carriers are described, for example, in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference. The composition may also include, for example, micelles or liposomes, or some other encapsulated form.

[0125] The specific dose can be adjusted according to the subject's disease state, age, body weight, general health, sex, and diet, administration interval, administration route, excretion rate, and drug combination. Any of the above dosage forms containing an effective amount is well within the scope of routine experimentation and therefore well within the skill of the present invention.

[0126] A variety of assays and model systems can be readily used to determine the therapeutic efficacy of treatment with the present technology.

[0127] For the indicated conditions, the test subject exhibits a 10%, 20%, 30%, 50% or more reduction, up to 75-90%, or 95% or more reduction in one or more symptom(s) caused by or associated with the disorder in the subject, compared to a placebo-treated or other suitable control subject.

[0128] In another aspect, the present technology provides a method of treating cancer by administering an effective amount of a targeting composition according to formula (II) to a subject having cancer. The cancers contemplated herein for treatment are not limited, since the cancer cell targeting agent can be selected to target any of a wide range of cancers. 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 composition described herein is usually 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., into a certain 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 breast, lung, stomach, intestine, prostate, ovary, cervix, pancreas, kidney, liver, skin, lymph, bone, bladder, uterus, colon, rectum, and brain. Cancer can also include the presence of one or more carcinomas, sarcomas, lymphomas, blastomas, or teratomas (germ cell tumors). Cancer can also be in the form of leukemia. In some embodiments, the cancer is triple-negative breast cancer.

[0129] As is well known in the art, the dosage of the active ingredient(s) generally depends on the disorder or condition being treated, the extent 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, a suitable dosage of the targeting composition may be precisely at least, e.g., 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. The dose may be greater 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 bounded by any of the exemplary doses set forth above. Furthermore, the compositions may be administered in the amounts indicated by any suitable schedule, such as once, twice or three times daily or every other day for 1, 2, 3, 4, or 5 days, or for 1, 2, 3, 4, or 4 weeks, or for 1, 2, 3, 4, 5, or 6 months of total treatment, or within any time frame therebetween. Alternatively, or additionally, the compositions can be administered until a desired change in the disorder or condition is achieved, or at such time as is believed to provide a prophylactic effect.

[0130] The examples herein are provided to illustrate the benefits of the present technology and to further assist those skilled in the art in preparing or using the compounds of the present technology or their salts, pharmaceutical compositions, derivatives, prodrugs, or tautomeric forms.The examples herein are also presented to more fully illustrate the preferred aspects 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 be incorporated into any of the variations, aspects, or embodiments of the present technology described above.These variations, aspects, or embodiments can also further include or be incorporated into any or all of the variations of the other variations, aspects, or embodiments of the present technology. EXAMPLES

[0131] Exemplary synthetic procedures and characterization Materials and Instrumentation. All solvents and reagents were purchased from commercial sources and used without further purification when administered unless otherwise indicated. Solvents indicated as "dry" were obtained after storage over 3 Å molecular sieves. Metal salts were purchased from Strem Chemicals (Newburyport, MA) to obtain 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 (on a trace metals basis, Beantown Chemical, Hudson, NH). Hydrochloric acid (BDH Aristar Plus, VWR, Radnor, PA) and nitric acid (Optima, ThermoFisher Scientific, Waltham, MA) were of trace metals grade. 225Chelex 100 (sodium form, 50-100 mesh) and human serum used for Ac-complex challenge assays were purchased from Sigma Aldrich (St. Louis, MO). Deionized water (≧18 MΩcm) was prepared on-site using Millipore Direct-Q® 3UV or Elga Purelab Flex 2 water purification systems.

[0132] Reactions were monitored by thin layer chromatography (TLC, Whatman UV254 aluminum-backed silica gel). The HPLC system used for compound analysis and purification consisted of a CBM-20A communication bus module, LC-20AP (preparative) or LC-20AT (analytical) pump, and SPD-20AV UV / Vis detector monitoring at 270 nm (Shimadzu Corporation, Japan). Analytical chromatography was performed using an Ultra Aqueous C18 column, 100 Å, 5 μm, 250 mm×4.6 mm (Restek, Bellefonte, PA) at a flow rate of 1.0 mL / min unless otherwise indicated. Purification was performed using an Epic Polar preparative column, 120 Å, 10 μm, 25 cm×20 mm (ES Industries, West Berlin, NJ) at a flow rate of 14 mL / min unless otherwise indicated. A gradient HPLC method was used with a binary mobile phase containing HO (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 system 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 are reported in ppm. 1 H and 13 C NMR spectra were referenced to a TMS internal standard (0 ppm), the residual solvent peak, or an acetonitrile internal standard (2.06 ppm in D2O spectra). 19 F NMR spectra were referenced to a monofluorobenzene internal standard (-113.15 ppm). 1Splitting of proton resonances in H spectra are defined as s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dt=triplet doublet, td=double triplet, and br=broad. IR spectroscopy was performed on KBr pellets of 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 / visible 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).

[0133] Synthesis and characterization of Macropa complexes, 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] were purchased from EMD Millipore (Darmstadt, Germany) or according to literature protocols.

[0104] The compound was prepared using 1,7,10,16-tetraoxa-4,13-diazacyclooctadecane (7), synthesized by Sigma-Aldrich. Chelidamic acid 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 6-chloromethylpyridine-2-carboxylic acid methyl ester (8),

[0102] was prepared according to the literature protocol indicated.

[0134] [La(macropa)] 2+ Preparation of.

[0135] [ka] To a suspension of H2macropa·2HCl·4H2O (0.0233 g, 0.034 mmol) in 2-propanol (0.6 mL) was added triethylamine (20 μL, 0.143 mmol). The pale-gold solution was heated at reflux for 25 min, after which a solution of La(ClO4)3·6H2O (0.0209 g, 0.038 mmol) in 2-propanol (0.5 mL) was added dropwise. A precipitate formed immediately. The cream suspension was stirred at reflux for an additional 1.5 h, cooled and centrifuged. The supernatant was removed and the pellet was washed with 2-propanol (2 × 1 mL) and then air-dried on filter paper to give the title complex as a light tan solid (0.0177 g) containing 0.64 equivalents of 2-propanol. 1 H NMR (500 MHz, D2O, pD ≈ 9) δ= 7.87 (t, J = 7.8 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.39 (d, J = 7.6 Hz, 2H), 5.21 (d, J = 15.7 Hz, 2H), 4.44 (t, J = 11.6 Hz, 2H), 4.09 (t, J = 11.2 Hz, 4H), 4.01 (t, J = 10.4 Hz, 2H), 3.74 (d, J = 9.9 Hz, 2H), 3.65-3.60 (m, 4H), 3.58-3.47 (m, 4H), 3.44 (d, J = 10.8 Hz, 2H), 2.75 (td, J = 13.1, 2.7 Hz, 2H), 2.56 (d, J = 13.9 Hz, 2H), 2.38 (d, J = 14.0 Hz, 2H). 13 C{ 1H} APT NMR (126 MHz, DO, pD ≒ 9) δ = 172.62, 158.70, 150.19, 140.94, 126.89, 122.32, 71.88, 70.12, 69.20, 68.05, 60.14, 56.08, 54.01. EA found: C, 35.16; H, 4.73; N, 5.91. C 26 H 35 Calculated for LaN4O8·2ClO4·2H2O·0.64iPrOH: C, 35.53; H, 4.71; N, 5.94. IR (cm -1 ): 3443, 2913, 1630, 1596, 1461, 1370, 1265, 1083, 948, 839, 770, 678, 617, 513. HPLC t R = 18.104 minutes (Method A). HRMS (m / z): 669.14289, 335.07519; [C 26 H 34 LaN4O8] + and [C 26 H 35 LaN4O8] 2+ Calculated values ​​are: 669.14346, 335.07537 respectively.

[0136] [Lu (macropa)] + Preparation of.

[0137] [ka] To a suspension of H2macropa·2HCl·4H2O (0.0730 g, 0.108 mmol) in 2-propanol (2 mL) was added triethylamine (61.5 μL, 0.441 mmol). The pale-gold solution was heated under reflux for 25 min, after which a solution of Lu(ClO4)3 (0.1372 g, 0.118 mmol Lu) in 2-propanol (1.8 mL) was added dropwise. A precipitate formed immediately. After stirring at reflux for an additional 1 h, the cream-colored suspension was ground at RT for 20 h and then centrifuged. The supernatant was removed and the pellet was washed with 2-propanol (2 × 2 mL) and then air-dried on filter paper to give the title complex as a light tan solid (0.0605 g) containing the remaining 2-propanol and triethylamine salt. 1 H NMR (600 MHz, D2O, pD ≈ 7-8) δ= 7.85 (t, J = 7.7 Hz, 2H), 7.52 (d, J = 7.8 Hz, 2H), 7.37 (d, J = 7.6 Hz, 2H), 4.68 (d, J = 16.3 Hz, 2H), 4.56 (td, J = 11.2, 1.7 Hz, 2H), 4.42-4.38 (m, 2H), 4.23-4.19 (m, 6H), 4.07 (d, J = 16.3 Hz, 2H), 3.96-3.87 (m, 2H), 3.71-3.63 (m, 4H), 3.38 (td, J = 10.0, 4.7 Hz, 2H), 3.00 (m, 2H), 2.93 (d, J = 13.1 Hz, 2H), 2.52 (dt, J = 14.8, 4.5 Hz, 2H). 13 C{ 1 H} APT NMR (126 MHz, D2O, pD ≒ 7-8) δ= 172.13, 158.67, 148.98, 141.81, 127.38, 122.83, 75.33, 73.12, 71.97, 71.70, 64.65, 57.37, 55.08.IR (cm -1 ): 3400, 1639, 1396, 1274, 1091, 913, 770, 678, 622. HPLC t R= not stable (Method A). HRMS (m / z): 705.17772; [C 26 H 34 LuN4O8] + Calculated value: 705.17788.

[0138] Preparation of dimethyl 4-aminopyridine-2,6-dicarboxylate (4).

[0139] [ka] Dimethyl 4-azidopyridine-2,6-dicarboxylate (3, 0.9445 g, 4.0 mmol), 10% Pd / C (0.1419 g), and DCM:MeOH (1:1, 18 mL) were combined in a round-bottom flask. After purging the flask with a balloon of H2, the reaction was stirred vigorously at room temperature under H2 atmosphere for 46 h. The grey mixture was diluted with DMF (450 mL) and filtered through a pad of Celite. After subsequent filtration through a 0.22 μm nylon membrane, the filtrate was concentrated under reduced pressure at 60 °C and further dried in vacuum to give 4 as a light tan solid (0.824 g, 98% yield). 1 H NMR (500 MHz, DMSO-d6): δ= 7.36 (s, 2 H), 6.72 (s, 2 H), 3.84 (s, 6 H). 13 C{ 1 H} APT NMR (126 MHz, DMSO-d6): δ= 165.51, 156.24, 148.05, 111.99, 52.29. IR (cm -1 ): 3409, 3339, 3230, 1726, 1639, 1591, 1443, 1265, 996, 939, 787, 630, 543. HPLC t R = 9.369 minutes (Method B). HRMS (m / z): 211.07213 [M + H] + ; Calculated value: 211.07133.

[0140] Preparation of ethyl 4-amino-6-(hydroxymethyl)picolinate (5).

[0141] [ka] To a refluxing suspension of 4 (0.677 g, 3.22 mmol) in anhydrous EtOH (27 mL) was added NaBH4 (0.1745 g, 4.61 mmol) in small portions for 1 h to give a pale yellow suspension. The reaction was then quenched with acetone (32 mL) and concentrated under reduced pressure at 60 °C to a tan solid. The crude product was dissolved in H2O (60 mL) and washed with ethyl acetate (4 x 150 mL). The combined organics were dried over sodium sulfate and concentrated under reduced pressure at 40 °C. Further drying in vacuum afforded 5 as a pale yellow solid (0.310 g, 49% yield). 1 H NMR (300 MHz, DMSO-d6): δ= 7.07 (d, J = 2.1 Hz, 1H), 6.78 (m, 1H), 6.32 (s, 2H), 5.30 (t, J = 5.8 Hz, 1H), 4.39 (d, J = 5.6 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13 C APT NMR (126 MHz, DMSO-d6) δ= 165.57, 162.38, 155.68, 147.25, 108.50, 107.01, 63.95, 60.61, 14.24. -1 ): 3439, 3217, 2974, 2917, 1717, 1643, 1600, 1465, 1396, 1378, 1239, 1135, 1022, 974, 865, 783. HPLC t R = 8.461 min (Method B). HRMS (m / z): 197.09288 [M + H] + ; Calculated value: 197.09207.

[0142] Preparation of ethyl 4-amino-6-(chloromethyl)picolinate (6).

[0143] [ka] A mixture of thionyl chloride (2.5 mL) and 5 (0.301 g, 1.53 mmol) was stirred in an ice bath for 1 h, then at RT for 30 min. The yellow-orange emulsion was concentrated under reduced pressure at 40 °C to an oily residue. The residue was neutralized with saturated aqueous NaHCO3 (12 mL) and then extracted with ethyl acetate (75 mL). The organic extract was washed with HO (2 mL), dried over sodium sulfate, and concentrated under reduced pressure at 40 °C. Further drying in vacuum gave 6 as an amber wax (0.287 g, 80% yield, corrected for residual ethyl acetate). 1 H NMR (500 MHz, DMSO-d6) δ= 7.18 (d, J = 2.1 Hz, 1H), 6.78 (d, J = 2.1 Hz, 1H), 6.62 (br s, 2H), 4.62 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13 C{ 1 IR (cm -1 ): 3452, 3322, 3209, 2978, 2922, 1726, 1639, 1604, 1513, 1465, 1378, 1248, 1126, 1026, 983, 861, 783, 752, 700. HPLC t R = 12.364 minutes (Method B). HRMS (m / z): 215.05903 [M + H] + ; Calculated value: 215.05818.

[0144] Preparation of methyl 6-((1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)picolinate (9·2TFA·1H2O).

[0145] [ka] A clear and colorless solution of 1,7,10,16-tetraoxa-4,13-diazacyclooctadecane (7, 1.9688 g, 7.5 mmol) and diisopropylethylamine (0.8354 g, 6.5 mmol) in dry ACN (1.075 L) at 75 °C was added dropwise to a solution of 6 (0.9255 g, 5.0 mmol) in dry ACN (125 mL) over 2 h 40 min. The flask was then equipped with a condenser and drying tube, and the slightly yellow solution was heated under reflux for 42 h. The dark-gold solution containing a fine, white precipitate was then concentrated under reduced pressure at 60 °C to an amber oil. To the crude oil was added 10% MeOH / H2O containing 0.1% TFA (10 mL). The slight suspension was filtered, and the filtrate was purified by preparative HPLC (Method A). The pure fractions were combined, concentrated under reduced pressure at 60° C., and then lyophilized to give 9 (1.6350 g, 50% yield) as a pale orange solid. 1 H NMR (500 MHz, DMSO-d6) δ= 8.75 (br s, 2H), 8.17-8.06 (m, 2H), 7.83 (dd, J = 7.4, 1.5 Hz, 1H), 4.68 (br s, 2H), 3.91 (s, 3H), 3.85 (br t, J = 5.1 Hz, 4H), 3.69 (t, J = 5.1 Hz, 4H), 3.59 (br s, 8H), 3.50 (br s, 4H), 3.23 (br t, J = 5.1 Hz, 4H). 13 C{ 1 H} APT NMR (126 MHz, DMSO-d6) δ 164.68, 158.78-157.98 (q, TFA), 151.44, 147.13, 139.01, 128.63, 124.87, 120.08-113.01 (q, TFA), 69.33, 69.00, 65.31, 64.60, 56.43, 53.29, 52.67, 46.32. 19F NMR (470 MHz, DMSO-d6) δ = -73.84. EA found: C, 43.88; H, 5.29; N, 6.28. C 20 H 33 N3O 6· Calculated for 2CF3COOH·1H2O: C, 43.84; H, 5.67; N, 6.39. HPLC t R = 12.372 minutes (Method B). HRMS (m / z): 412.24568 [M + H] + ; Calculated value: 412.24421.

[0146] Preparation of ethyl 4-amino-6-((16-((6-(methoxycarbonyl)pyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)picolinate (10).

[0147] [ka] In a round bottom flask equipped with a condenser and drying tube were added 9 (0.4210 g, 0.64 mmol), Na2CO3 (0.3400 g, 3.2 mmol), and dry ACN (10 mL). The pale yellow suspension was heated to reflux for 15 min, after which 6 (0.1508 g, 0.70 mmol, corrected for remaining ethyl acetate) was added as a slight suspension in dry ACN (3.5 mL). The mixture was heated under reflux for 44 h and then filtered. The orange filtrate was concentrated under reduced pressure at 60 °C to an orange brown oil (0.612 g), which was used in the next step without further purification. HRMS (m / z): 590.32021 [M+H] + ;Calc:590.31844.

[0148] Preparation of 4-amino-6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)picolinic acid (11·4TFA).

[0149] [ka] Compound 10 (0.612 g) was dissolved in 6 M HCl (7 mL) and heated at 90° C. for 17 h. The orange-brown solution containing a slight precipitate was concentrated under reduced pressure at 60° C. to a light tan 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 and concentrated under reduced pressure at 60° C., then lyophilized to give 11 as an off-white solid (0.2974 g, 46% yield over two 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 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 minutes (Method B); 11.546 minutes (Method D). HRMS (m / z): 548.26883 [M + H] + ; Calculated value: 548.27149.

[0150] Preparation of 6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)-4-isothiocyanatopicolinic acid (12, macropa-NCS).

[0151] [ka] 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, after which CSCl2 (305 μL 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 in small portions in 10% ACN / H2O containing 0.2% TFA (8 mL total), filtered, and immediately purified by preparative HPLC using Method C.

[0108] Pure fractions were combined and concentrated under reduced pressure at RT to remove the organic solvent, then lyophilized. Fractions that could not be immediately concentrated 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 Drierite jar. A sample of 12 spiked with known concentrations of fluorobenzene was analyzed. 1 H NMR and 19 12 was estimated to be isolated as the tetra-TFA salt by calculation from the F NMR spectrum. 1H NMR (400 MHz, DMSO-d6) δ= 8.17-8.06 (m, 2H), 8.00 (sw / fine splitting, 1H), 7.84 (d, J = 1.5 Hz, 1H), 7.81-7.75 (dw / 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 F NMR (470 MHz, DMSO-d6) δ= -74.17. IR (cm -1 ): approx. 3500-2800, 2083, 2026, 1735, 1670, 1591, 1448, 1183, 1130, 796, 717. HPLC t R = 15.053 minutes (Method B); 13.885 minutes (Method D). HRMS (m / z): 590.22600 [M + H] + ; Calculated value: 590.22791.

[0152] Preparation of 6-((16-((6-carboxypyridin-2-yl)methyl)-1,4,10,13-tetraoxa-7,16-diazacyclooctadecan-7-yl)methyl)-4-(3-methylthioureido)picolinic acid (13, macropa-NHC(S)NHCH3).

[0153] [ka] Compound 12 was prepared as previously described using 0.0873 g (0.087 mmol) of 11, except that the purification step was omitted. Instead, 2M methylamine in THF (4 mL) was added directly to the crude solid. The tan-orange suspension was stirred at RT for 2 h, then concentrated under reduced pressure at RT to a pale pink solid. The solid was dissolved in 10% ACN / H2O containing 0.2% TFA (2 mL), filtered, and purified by preparative HPLC using method C. Pure fractions were combined and concentrated under reduced pressure at 50° C. to remove organic solvents, then lyophilized. The slightly sticky dark-gold solid was then recrystallized from ACN with Et2O. The suspension was centrifuged and the pellet was washed with EtO (2×1.5 mL) and dried in vacuum to give 13 as a tan powder (0.0166 g, 22% unoptimized yield from 11). 1 H NMR (600 MHz, DMSO-d6) δ= 10.56 (s, 1H), 8.64 (br s, 1H), 8.26 (s, 1H), 8.16 (s, 1H), 8.13-8.02 (m, 2H), 7.81-7.73 (d, J = 7.40 Hz, 1H), 4.74-4.48 (m, 4H), 3.82 (br s, 8H), 3.57 (br s, 8H), 3.54-3.25 (m, 8 H), 2.97 (d, J = 4.4 Hz, 4H). 13 C{ 1 H} NMR (126 MHz, DMSO-d6) δ 180.71, 165.44, 165.39, 158.77-157.95 (q, TFA), 151.04, 150.96, 149.79, 147.95, 147.71, 139.22, 127.76, 124.55, 119.68-112.66 (q, TFA), 116.45, 114.85, 69.36, 64.52, 64.50, 57.00, 56.75, 53.42, 53.37, 31.02. 19 F NMR (470 MHz, DMSO-d6) δ = -74.49. EA found: C, 44.66; H, 5.36; N, 9.83. C28 H 40 N6O8S · 2CF3COOH · Calculated for 1H2O: C, 44.34; H, 5.12; N, 9.70. HPLC t R = 14.067 minutes (Method B). HRMS (m / z): 621.26799 [M + H] + ; Calculated value: 621.27011.

[0154] X-ray diffraction studies. Single crystals of H2macropa·2HCl·4H2O suitable for X-ray diffraction were grown from a saturated H2O:acetone (1:5) solution after standing at room temperature. Single crystals of [La(Hmacropa)(H2O)]·(ClO4)2 were grown by vapor diffusion of THF into an acidified 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.

[0155] X-ray diffraction data for H2macropa·2HCl·4H2O, [La(Hmacropa)(H2O)]·(ClO4)2, and [Lu(macropa)]·ClO4·DMF were collected on a Bruker APEX 2 CCD Kappa diffractometer (Mo Kα, λ = 0.71073 Å) at 223 K. The structures were analyzed using SHELXT

[0109] After analyzing the phasing method using SHELXL and establishing an improvement strategy,

[0110] F for all data using full-matrix least squares 2 was refined to

[0111] All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included in the model at their geometrically calculated positions and refined using a riding model. Nitrogen- and oxygen-bonded hydrogen atoms were placed in a 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 atom to which they are connected (1.5 times for methyl groups). In the case of [La(Hmacropa)(H2O)]·(ClO4)2, a partially occupied solvent molecule of water was included in the unit cell but could not be modeled satisfactorily. This solvent was therefore treated as a diffuse contribution to the overall scattering, without specific atomic positions, by the solvent masking feature in Olex2.

[0112]

[0156] 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 aqueous NMe4OH. Ionic strength was set at 100 mM using NMe4Cl. Stock solutions of LaCl3·6.8H2O (40 mM) and LuCl3·6H2O (21 mM) were prepared in 1 mM HCl. Stock solutions of H2macropa·2HCl·4H2O (8.8 mM) were prepared in MOPS buffer. From these stock solutions, titration solutions containing macropa (100 μM) and LaCl3 or LuCl3 were prepared in MOPS. Each metal ion titration was performed at RT by adding 5–10 μL aliquots of titrant to a cuvette containing 3000 μL of macropa (100 μM) in MOPS. Each sample was equilibrated for 5 min after each addition before acquiring a spectrum. Metal ion complex formation in macropa λ max The titrant was added until no further change in the spectrum was detected.

[0157] Macropa La 3+ and Lu 3+Kinetic inactivity of complexes: transchelation challenge. A stock solution of ethylenediaminetetraacetic acid (EDTA, 100 mM) was made in MOPS buffer (prepared as described above) by adjusting the pH of the initial suspension to 6.6 with aqueous NMe4OH. A stock solution of diethylenetriaminepentaacetic acid (DTPA, 125 mM) was prepared in HO by adjusting the pH to 7.4 as described for EDTA. This solution was serially diluted with HO to produce 12.5 mM and 1.25 mM solutions of DTPA.

[0158] macropa preformed La 3+ and Lu 3+ The complexes were challenged with EDTA. The challenge was initiated by adding an aliquot of a solution containing EDTA (98.7 mM) and macropa (100 μM) in MOPS buffer to each solution of the complex. The final M:macropa:EDTA ratio was approximately 1:1:20 (La) and 1:1:10 (Lu). The solutions were repeatedly analyzed by UV spectrometry over a period of 21 days for any spectral changes. The final pH of each solution was between 7.18 and 7.25.

[0159] La 3+ The complex formed in situ between LaCl3 and macropa was challenged more rigorously with an excess of DTPA. A solution containing 500 μM of the complex, prepared with the LaCl3 and macropa stock solutions described above, was allowed to equilibrate for 5 min. It was then split 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 of DTPA and 100 μM concentration of macropa. These solutions were repeatedly analyzed by UV spectrometry over a period of 21 days for any spectral changes. The final pH of each solution was between 7.11 and 7.42.

[0160] Macropa and DOTA 225 Ac radiolabel.

[0161] overview. 225 Ac and 225 Ra was produced by spallation reactions of uranium carbide and separated downstream from other radionuclides by mass separators using the Isotope Separator and Accelerator (ISAC) online isotope separation (ISOL) facility at TRIUMF (Vancouver, BC, Canada) and collected according to literature protocols. [103,104] Next, 225 Ac, DGA column [105,106] (Branches, 50-100 μm, Eichrom Technologies LLC) 225 The eluate was separated from Ra and prepared in 0.05 M HNO3 for use in radiolabeling experiments. Aluminum-backed TLC plates (silica gel 60, F 254 , EMD Millipore, Darmstadt, Germany) 225 The progress of the Ac radiolabeling reaction was analyzed. Instant thin-layer chromatography paper impregnated with silica gel (iTLC-SG, Agilent Technologies, Mississauga, ON, Canada) was used to 3+ and serum stability challenges. The TLC plates were developed and then counted after at least 8 h in a BioScan series 200 imaging scanner equipped with a BioScan Autochanger 1000 and WinScan software to allow time for the daughter isotopes to decay completely and to confirm that the measured radioactive signal was greater than that of the parent. 225 Guaranteed to be generated by Ac. 225 Ac, 221 Fr, and 213 Quantitative radioactivity measurement of Bi in a NIST-traceable mixture 133 Ba and 152The concentrations were determined by γ-spectrometry using a high-purity germanium (HPGe) detector (Canberra GR1520, Meriden, CT) calibrated with a Eu source. Detector dead time was kept below 10% for all measurements. Data were analyzed using Genie2000 software (v3.4, Canberra, Meriden, CT).

[0162] Concentration dependence. Various concentrations of macropa and DOTA were 225 Ac 3+ The lowest concentration at which >95% radiolabeling occurred was determined. -3 ~10 -8 M) and H4DOTA (10 -3 , 10 -5 , and 10 -7 Stock solutions of ligand (10 μL) and 225 Ac (10–26 kBq, 10–30 μL) was added sequentially to NHOAc buffer (pH 6, 0.15 M, 150 μL) to obtain a final ligand concentration of 5.3 × 10 for macropa. -5 ~5.9×10 -10 5.9 × 10 for M and DOTA -5 ~5.9×10 -9 M was obtained. The final pH of all labeling reactions was between 5.5 and 6. The reaction solutions were maintained at ambient temperature or at 80°C. The progress of the reactions was monitored at 5 and 30 min by spotting 3-5 μL of the reaction solutions onto TLC plates. The 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)] - is the baseline (R F =0) and does not undergo any chelation 225 Ac( 225 Ac-citrate) moved with the solvent front (R F= 1). Radiochemical yields (RCYs) were calculated by integrating the areas under the peaks in the radiochromatograms and 225 Ac-complex (R F = 0) by dividing the total counts integrated along the length of the TLC plate.

[0163] Macropa and DOTA 225 Kinetic inactivity of Ac complexes.

[0164] Summary. A stock solution of La(NO3)3 (0.001M or 0.1M) was prepared in H2O. Macropa (10 -5 M stock solution 10μL; 1.0×10 -10 mole) or DOTA(10 -3 M stock solution 10μL; 1.0×10 -8 moles) and 225 Radiolabeled samples containing Ac (10 μL, 26 kBq) were diluted with a 50-fold molar excess of La 3+ (5 μL of 0.001M or 0.1M stock solution was added to the solutions containing macropa and DOTA, respectively). The solutions were kept at room temperature and analyzed by iTLC at several time points over a period of 8 days. The iTLC plate was developed using citric acid (0.05M, pH 5) as the eluent. Under these conditions, [ 225 Ac(macropa)] + and 225 Ac(DOTA)] - remains at baseline (R F =0), any non-chelated 225 Ac( 225 Ac-citrate) moved with the solvent front (R F = 1). The percentage of the complex that remains unchanged was determined by integrating the areas under the peaks in the radiochromatogram and 225 Ac-complex (R F = 0) by dividing the total counts integrated along the length of the iTLC plate.

[0165] La 3+ Transmetallation reaction by [ 225 Ac(macropa)] + and 225 Ac(DOTA)] - 10 for macropa and DOTA, respectively. -5 M and 10 -3 Prepare the final ligand concentration of 5.9 x 10 using 10 µL of M stock solution. -7 M (macropa) and 5.9 × 10 -5 M(DOTA) was obtained. After confirming 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 labeling reaction volume) was added to each respective radiolabeled solution. A control solution was also prepared, substituting water for the ligand. The solutions were monitored by iTLC over a period of 8 days. The plate was developed with EDTA (50 mM, pH 5) as the eluent. Under these conditions, [ 225 Ac(macropa)] + and 225 Ac(DOTA)] - The complex remains at baseline (R F = 0), any transchelated by serum 225 Ac( 225 Ac-EDTA) moved with the solvent front (R F = 1). The percentage of the complex that remained unchanged was calculated.

[0166] Macropa and DOTA 225 In vivo biodistribution of Ac complexes. All experiments were approved by the Institutional Animal Care Committee (IACC) of the University of British Columbia and were performed in accordance with the Canadian Council on Animal Care Guidelines. A total of nine female C57BL / 6 mice (6-8 weeks old, 20-25 g) were used for biodistribution studies of each radiometal complex, with n=3 for each time point.

[0167] Macropa (100 μL of a 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 metals grade). After 5 min at ambient temperature, the reaction solution was analyzed by TLC (0.4 M sodium citrate, pH 4, as eluent), which confirmed a radiochemical yield of >95%. The reaction was allowed to proceed overnight, and the radiochemical yield was again confirmed to be >95% the following morning. During this period, mice were anesthetized with 2% isoflurane and [ 225 Ac(macropa)] + Approximately 100 μL (10-15 kBq) of the complex was injected into the tail vein of each mouse. After injection, mice were allowed to recover and move freely in their cages, and were euthanized by CO2 inhalation 15 min, 1 h, or 5 h after injection (n=3 for each time point). Blood was collected by cardiac puncture and placed into appropriate test tubes for scintillation counting. Tissues collected included heart, liver, kidney, lung, small intestine, large intestine, brain, bladder, spleen, stomach, pancreas, bone, thyroid, tail, urine, and feces. Tissues were weighed and then counted in a calibrated gamma counter (Packard, Cobra II model 5002) using three energy windows: 60-120 keV (window A), 180-260 keV (window B), and 400-480 keV (window C). Measurements were taken immediately after sacrifice and 7 days later; counts were decay corrected from time of injection and then converted to percentage of injected dose (%ID) per gram of tissue (%ID / g). No differences between the data were shown; therefore, biodistribution was reported using data obtained immediately using window A.

[0168] [ 225 Ac(DOTA)] - and 225 The biodistribution test of Ac(NO3)3 was carried out as follows: 225 Ac(macropa)] +The above was carried out as described above. 225 Ac(DOTA) - of, 225 A solution was prepared by adding Ac(NO3)3 (338 μL, 1.1 MBq) to a solution of DOTA (100 μg, 20 mg / mL in H2O) in NHOAc (467 μL, 0.15 M, pH 7). The pH of the solution was adjusted to 7 with NHOAc (150 μL, 1 M, pH 7) and the solution was heated at 85 °C for 45 min. RCY >99% was confirmed by TLC as previously described. 225 Ac(DOTA)] - was diluted with saline to a final concentration of 0.05MBq / 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)] - The injection was done in the same manner as above. 225 Ac(DOTA)] - One mouse was euthanized at 5 h during the study and died immediately after injection. 225 One mouse died during the Ac(NO3)3 test that was euthanized at 1 h.

[0169] Hydrolysis of macropa-NCS and p-SCN-Bn-DOTA. Screw-capped vials containing approximately 1 mg of macropa-NCS (compound 12, n=4) or p-SCN-Bn-DOTA (n=5) were added with 1 mL of 0.1 M NaHCO3 buffer (pH 9.1) containing 0.154 M NaCl, which had been passed through a pre-equilibrated Chelex column. After stirring for 1 min, each solution was filtered through a 0.2 μm PES or PTFE membrane. 5 μL aliquots were removed from the vials at various time points over a period of 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 disappearance or negligible integration of the peak at 13.8 min (corresponding to 12) or 18.417 min (corresponding to p-SCN-Bn-DOTA). Linear regression performed on a plot of ln peak area versus time yielded a pseudo-first order rate constant (k obs ) was shown. 1 / 2 ) into equation t 1 / 2 =0.693 / k obs The half-life of each compound is reported as the mean ± 1 standard deviation.

[0170] La 3+ Titration of Macropa-NHC(S)NHCH3 conjugate with La, except that the stock solution of 13 (0.760 mM) was prepared in ACN instead of MOPS. 3+Titration of macropa-NHC(S)NHCH3 conjugate (13) with was carried out at pH 7.4 for macropa. The amount of ACN in the samples did not exceed 3.3% by volume. A waiting time of 3 min after addition of each aliquot was found to be sufficient for the samples to reach equilibrium before spectra acquisition. Complexation 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.

[0171] Kinetic inactivation of La-Macropa-NHC(S)NHCH3: Transchelation challenge. Solutions of diethylenetriaminepentaacetic acid (DTPA; 125 mM and 12.5 mM) were prepared in MOPS buffer (pH 7.4). MOPS solutions containing macropa-NHC(S)NHCH3 (126.7 μM, 16.7% by volume of ACN) and LaCl3 (126.2 μM) were prepared using the above stock solutions and equilibrated for 10 min. This was then split into cuvettes and diluted with 125 mM DTPA, 12.5 mM DTPA, or MOPS to generate solutions containing 1000-, 100-, or 0-fold excess of 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 a period of 21 days for any spectral changes. The final pH of each solution was between 7.42 and 7.49. Experiments were performed in triplicate.

[0172] Conjugation of Macropa-NCS and p-SCN-Bn DOTA to trastuzumab.

[0173] Summary. All glassware was washed overnight in 1M HCl. Saline (0.154M NaCl) and all buffers were passed through a Chelex-100 column pre-equilibrated with the appropriate buffer. Trastuzumab (Tmab, Genentech) was purified using a Zeba spin desalting column (2mL or 5mL, 40MWCO, Thermo Scientific, Waltham, MA) with saline as the mobile phase according to the manufacturer's protocol. The concentration of purified Tmab was determined by A 280 and ε 280 1.446mLmg -1 cm -1 The calculation was performed using the Beer-Lambert law.

[0107] Purified Tmab and Tmab conjugates were stored at 4°C.

[0174] Conjugation of Macropa-NCS to Tmab. A stock solution containing 4.4 mg / mL of macropa-NCS (12) 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) was added 12 (52 μL) and NaHCO3 buffer (266 μL) 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 in 16-fold molar excess over Tmab based on the molecular weight of 1045.76 g / mol for 12 (tetra-TFA salt). The pH of this solution was between 8 and 9 by litmus paper. The solution was gently rocked at room temperature for 17.5 h and then purified using a spin column.

[0175] Conjugation of p-NCS-Bn-DOTA to Tmab. A stock solution containing 3.05 mg / mL of p-NCS-Bn-DOTA was prepared in H2O and stored at -80°C. To a portion of Tmab in saline (66 μL) was added p-NCS-Bn-DOTA (49 μL) and NaHCO3 buffer (274.5 μL) 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 over L), respectively. The pH of this solution was between 8 and 9 by litmus paper. The solution was gently rocked at room temperature for 17.5 h and then purified using a spin column.

[0176] Determination of conjugate protein concentration by BCA assay. The concentrations of proteins in Macropa-Tmab and DOTA-Tmab conjugates were determined using the Pierce™ BCA Protein Assay Kit (Thermo Scientific, Waltham, MA, microplate protocol). Tmab was used as a protein standard. A 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 (r 2 = 0.9966). Protein concentrations of each conjugate were calculated from two independent dilutions, each measured in triplicate, and the results were averaged to give a protein concentration of 4.557 mg / mL for macropa-Tmab and 2.839 mg / mL for DOTA-Tmab.

[0177] Ligand-to-protein ratio analysis 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 procedures described elsewhere.

[0108] The purified Tmab and its conjugates were analyzed in duplicate and the [M+H] values ​​obtained from the chromatograms were + Mass signals were averaged for each compound. The ligand-to-protein (L:P) ratio for each conjugate was obtained by subtracting the molecular weight of the Tmab from that of the conjugate, followed by division by the mass of the bifunctional ligand.

[0178] Tmab conjugates 225 Ac radiolabeling and serum stability of the complexes.

[0179] Summary. Instant thin-layer chromatography paper impregnated with silica gel (iTLC-SG, Agilent Technologies, Mississauga, ON, Canada) was used to 225 The progress of the Ac radiolabeling reaction was monitored and serum stability was determined. TLC plates were developed as described below and then counted after at least 8 h in a BioScan System 200 imaging scanner equipped with a BioScan Autochanger 1000 and WinScan software to ensure that the time for the daughter isotope was completely decayed and the measured radioactive signal was consistent with that of the parent isotope. 225 It was guaranteed to be produced by Ac.

[0180] 225 Ac radiolabeling test. In a total reaction volume of 200 μL made with NH4OAc buffer (pH 6, 0.15 M), 225Ac (10 or 20 kBq, 7-10 μL) was mixed with 25-100 μg of macropa-Tmab (5.5-22 μL) or DOTA-Tmab (8.81-35.2 μL) and the pH was adjusted to approximately 5 with NaOH. A control solution was also prepared in which unmodified Tmab (25 μg) was substituted for the conjugate. The reaction solutions were kept at ambient temperature and analyzed at 5 min, 30 min, 1 h, 2 h, 3 h, and 4 h by spotting 8 μL in triplicate on an iTLC stripe. The stripe 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 was plated (R F =0) baseline and any unchelated 225 Ac( 225 Ac-citrate) moved with the solvent front (R F = 1). Radiochemical yields (RCYs) were calculated by integrating the areas under the peaks in the radiochromatogram. 225 Ac-complex (R F = 0) by dividing the total counts integrated along the length of the TLC plate.

[0181] In human serum 225 Stability of Ac-macropa-Tmab. 225 A solution of Ac-macropa-Tmab was prepared with 100 μg of protein. After confirmation by TLC that RCY>95% had been achieved, human serum was thawed to room temperature and added to the radiolabeled immune complex to obtain a solution containing 90% serum by volume. Samples were incubated at 37°C. At various time points over a 7-day period, aliquots (15-30 μL) were removed from the samples and spotted in triplicate on iTLC stripes. Stripes were developed with an EDTA (50 mM, pH 5.2) mobile phase and counted. Under these conditions, 225 Ac-macropa-Tmab remained at baseline (R F = 0), any transchelated by serum 225 Ac(225 Ac-EDTA) moved with the solvent front (R F = 1). The percentage of the complex that remained unchanged was calculated.

[0182] As an additional challenge, separate aliquots (39 μL) were also removed from serum samples on days 1 and 7 and mixed with 50 mM DTPA (pH 7, 13 μL) to remove any antibodies that were only loosely bound by the radioimmunocomplex. 225 Ac was challenged to dissociate. After incubating the solution at 37° C. for 15 min, aliquots (30 μL) were spotted in triplicate onto iTLC plates and developed with an EDTA (50 mM, pH 5.2) mobile phase. The percentage of complex that remained unchanged was calculated.

[0183] [ 225 Ac(macropa)] + , [ 225 Ac(DOTA)] - , and 225 In vivo biodistribution study of Ac(NO3)3.

[0184] Table 1. After intravenous injection in mice 225 Organ distribution of Ac complexes. Adult C57BL / 6 mice were cultured in a 30-well plate. 225 Ac(macropa)] + , [ 225 Ac(DOTA)] - ,or 225 Mice were injected with Ac(NO3)3 and sacrificed 15 min, 1 h, or 5 h later. Values ​​for each time point were obtained as %ID / g (n=3) using energy window A (60-120 keV). [Table 1] JPEG0007675500000031.jpg139168

[0185] Table 2. After intravenous injection in mice 225 Organ distribution of Ac complexes. Adult C57BL / 6 mice were cultured in a 30-well plate. 225 Ac(macropa)]+ , [ 225 Ac(DOTA)] - ,or 225 Mice were injected with Ac(NO3)3 and sacrificed 15 min, 1 h, or 5 h later. Values ​​for each time point were obtained as %ID / g (n=3) using energy window B (180-260 keV). [Table 2] JPEG0007675500000033.jpg138168

[0186] Table 3. After intravenous injection in mice 225 Organ distribution of Ac complexes. Adult C57BL / 6 mice were cultured in a 30-well plate. 225 Ac(macropa)] + , [ 225 Ac(DOTA)] - ,or 225 Mice were injected with Ac(NO3)3 and sacrificed 15 min, 1 h, or 5 h later. Values ​​for each time point were obtained as %ID / g (n=3) using the energy window C (400-480 keV). [Table 3] JPEG0007675500000035.jpg140169

[0187] 225 In vivo study of Ac-macropa-Tmab.

[0188] At the time points indicated in Table 4 below, aliquots of the complex in serum were removed and analyzed directly by radio-TLC or were first mixed with an excess of DTPA to remove any loosely bound complexes. 225 The decay-corrected values ​​shown are the R on the TLC plate after exposure to the EDTA mobile phase. FThe percent activity with complexes at 0.05% is expressed as % activity with complexes at 0.05%. The reported uncertainties (±1 SD) were derived from spotting triplicate TLC plates at each time point. The percent of intact complex remaining was not significantly different for samples that were DTPA challenged versus samples that were not DTPA challenged (p>0.05, two-tailed t-test). These results indicate that 225 It is demonstrated that Ac remains strongly bound by macropa-Tmab in human serum over a period of 7 days.

[0189] Table 4. Human serum concentrations at 37°C 225 Complex stability of Ac-macropa-Tmab (% of unchanged complex remaining). [Table 4]

[0190] Characterization of 18-membered macrocyclic ligands for ion chelation. Radium-223( 223 Actinium-225 (Ra) was the first therapeutic alpha (α)-emitting radionuclide approved for clinical use in cancer patients and is effective in eradicating bone metastases. To exploit the therapeutic potential of α particles for soft tissue metastases, a strategy of targeted α particle therapy (TAT) has emerged in which lethal α-emitting radionuclides are conjugated to tumor-targeting vectors using bifunctional chelators to selectively deliver cytotoxic α radiation to cancer cells. 225 Ac) was tested for use in TAT because it has a long half-life of 10 days that is compatible with antibody-based targeting vectors and produces four high-energy alpha emissions that are highly lethal to cells. The 12-membered tetraazamacrocycle H4DOTA is currently 225 Ac 3+ The current state of the art for chelation of ions, however, when the ionic radius of the metal ion increases, the thermodynamic stability of the complex with H4DOTA decreases and this ligand is 3+It has been shown that the macrocyclic complexes of the present technology are not optimal for their chelation of ions (up to +3 ions in the periodic table). The macrocyclic complexes of the present technology show significant and unexpected improvements over known complexes, and the present examples (H2macropa and H2macropa-NCS; Scheme 1) demonstrate the improved chelation of the present technology. 225 An example is an Ac2-functional chelator.

[0191] [ka]

[0192] Previous studies have assessed the thermodynamic affinities of the entire lanthanide series, whereas the smaller Lu 3+ , Ca 2+ , and Cm 3+ The larger metal ion La 3+ , Pb 2+ , and Am 3+ It was shown to be selective for [24-26] Without wishing to be bound by theory, macropa is a large Ac 3+ It was thought that it should be able to efficiently chelate Ac-ions. Before evaluating its Ac-chelating properties, complex formation was confirmed using macropa and cold La. 3+ and Lu 3+ In these studies, the La 3+ , because it is slightly smaller but chemically similar (1.03 Å, CN6). 225 Ac 3+ macropa was used as a non-radioactive surrogate for the smaller Lu 3+ The complexation of the La ion (0.861 Å, CN6) was investigated to explore its size-selectivity. 3+ and Lu 3+ Titrations confirmed the high affinity of these metal ions for macropa at pH 7.4, which was consistent with the previously determined stability constants (log K LaL =14.99, logarithm K LuL=8.25).

[24] The kinetic inactivity of these complexes formed in situ was confirmed by Lu 3+ and La 3+ These were investigated by challenging them with excess amounts of ethylenediaminetetraacetic acid (EDTA) or diethylenetriaminepentaacetic acid (DTPA) chelators, which have a higher thermodynamic affinity for the ion than macropa.

[27] Lu 3+ The La ion was transchelated within 1 min by the addition of only 10 equivalents of EDTA, whereas the La 3+ The complex remained unchanged for 21 days in the presence of 1000 equivalents of DTPA. 3+ Despite the strong thermodynamic preference of DTPA for the transchelation of β-lactamase, the high level of kinetic inactivity of the macropa complex is demonstrated to inhibit this process on detectable time scales.

[0193] macropa La 3+ and Lu 3+ The complexes were isolated and their solid-state structures were elucidated by X-ray crystallography (Figures 1A-1D). 3+ and Lu 3+ The ion is present in the above 18-membered macrocycle, with the two picolinate arms located on the same side of the macrocycle. 3+ The coordination sphere of the ion is filled by 10 donors in macropa with both picolinate arms deprotonated; in contrast, the larger La 3+ The ion forms an 11-coordinate complex by incorporation of an inner-sphere water molecule through the macrocycle. Recent EXAFS studies have demonstrated that Ac 3+ The ability of macropa to form stable 11-coordinated complexes is particularly important because a coordination number of 11 has been demonstrated to be preferred in aqueous solution. [29,30]

[0194] Macropa is a larger, radioactive 225 Ac 3+Ion chelation was tested and compared with DOTA. Both ligands (59 μM) were diluted in 0.15 M NH4OAc buffer at pH 5.5-6. 225 Ac (26 kBq) and the complexation reaction was monitored by radio-TLC after 5 min. Surprisingly, macropa was found to be completely soluble in all 100% water after only 5 min at RT. 225 Complexed with Ac, DOTA was only 10% bound under these conditions. At a concentration 100-fold lower than macropa (0.59 μM), with an L:M ratio of only 1800, radiolabeling was more complete in 5 min at RT. At this concentration, DOTA 225 Collectively, these studies demonstrate that macropa exhibits superior radiolabeling kinetics at ambient temperature and sub-μM ligand concentrations, conditions where DOTA fails.

[0195] 225 The long half-life of Ac is due to its stable complex retention in vivo, resulting in the free 225 Ac 3+ It is necessary to avoid off-target damage to normal tissues resulting from the release of ribozymes. Furthermore, it is necessary to have a mechanism for the transmetallation and transchelation reactions. 225 The high stability of the Ac complex is essential. To determine the kinetic inactivity, 225 Ac(macropa)] + Since the high affinity of macropa for this metal ion has been established, La 3+ The challenge was performed with 50-fold excess of La 3+ , RT macropa 225 Ac radiolabeled solution (0.59 μM) was added over a period of 7 days. 225 98% of the Ac complex remained unchanged by radio-TLC, and a large molar equivalent of La 3+ teeth, 225 Ac 3+ This shows that the [ 225Ac(macropa)] + The stability of was also evaluated by radio-TLC. 225 Ac 3+ However, it was found that the nucleosomes remained bound by macropa for at least 8 days.

[0196] [ 225 Ac(macropa)] + Evaluation of biodistribution of the complex [ 225 Ac(macropa)] + The in vivo stability and biodistribution of 225 Ac(NO3)3 and [ 225 Ac(DOTA)] - C57BL / 6 mice were injected with 10-50 kBq of each radioactive metal complex via the tail vein and sacrificed 15 min, 1 h, or 5 h later. 225 The amount of Ac was quantified by gamma counting and reported as percent of injected dose per gram of tissue (%ID / g). The results of these studies are summarized in Tables 1-3. 225 The inadequate stability of Ac complexes was demonstrated in the liver, spleen, and bones of mice. 225 This is revealed by accumulation of Ac. [11,12,32] In Figure 2A, the unbound 225 Slow blood clearance and excretion are demonstrated in conjunction with large accumulations of Ac(NO3)3 in the liver and spleen. 225 Ac(macropa)] + The biodistribution profile of (Figure 3B) was 225 The distribution profile in the body is clearly different from that of Ac(NO3)3. 225 Ac(macropa)] + was rapidly cleared from the mice, with very little activity measured in the blood every hour after injection. The majority of the injected dose was excreted by the kidneys and was subsequently detected in the urine, with activity observed in mice 15 minutes and 1 hour after injection. 225 Ac(macropa)] +The results demonstrate moderate renal and bladder uptake of 225 Ac(macropa)] + did not accumulate in any organs over the time course of the study, and the complex was 225 Ac 3+ Its biodistribution profile was shown to be [ 225 Ac(DOTA)] - The biodistribution profile of α-amyloides was similar to that of α-amyloides (Figure 3C), which indicates that α-amyloides was 225 Ac 3+ It has been shown previously to hold. [7]

[0197] [ 225 Ac(macropa)] + Synthesis and characterization of TAT complexes [ 225 Ac(macropa)] + Due to the inherent stability of the complex, macropa was incorporated into tumor targeting constructs. To facilitate its conjugation, a reactive isothiocyanate functional group was installed on one of the picolinate arms of macropa to give the novel bifunctional ligand macropa-NCS (Scheme 1). As exemplified in the above references, macropa-NCS was synthesized over eight steps and characterized by conventional techniques. In the case of 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 and other cancers.

[33] With a biological half-life of several weeks [34,35] , Tmab is a long-lived 225 Ac is an ideal vector for shuttling radionuclides to tumor cells. 225 Ac-macropa-Tmab showed excellent stability in human serum at 37°C; after 7 days, >99% of the complex remained unchanged (Table 4). Collectively, these results suggest the potential of Ac-macropa-Tmab in antibody constructs as well as other cancer-targeting constructs.225 The effect of macropa as a chelator for Ac becomes clear.

[0198] 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, JP Bergerat, Curr. Clin. Pharmacol. 2008, 3, 51. 37. AP Kozikowski, F. Nan, P. Conti, J. Zhang, E. Ramadan, T. Bzdega, B. Wroblewska, JH Neale, S. Pshenichkin, JT Wroblewski, J. Med. Chem. 2001, 44, 298. 38. KP Maresca, SM Hillier, FJ Femia, D. Keith, C. Barone, JL Joyal, CN Zimmerman, AP Kozikowski, JA Barrett, WC Eckelman, et al., J. Med. Chem. 2009, 52, 347. 39. SM Hillier, KP Maresca, FJ Femia, JC Marquis, CA Foss, N. Nguyen, CN Zimmerman, JA Barrett, WC Eckelman, MG Pomper, et al., Cancer Res. 2009, 69, 6932. 40. JA Barrett, RE Coleman, SJ Goldsmith, S. Vallabhajosula, NA Petry, S. Cho, T. Armor, JB Stubbs, KP Maresca, MG 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, WDW Heston, J. Cell. Biochem. 2004, 91, 528. 43. MS Dennis, M. Zhang, Y. Gloria Meng, M. Kadkhodayan, D. Kirchhofer, D. Combs, LA Damico, J. Biol. Chem. 2002, 277, 35035. 44. CE Dumelin, S. Trussel, F. Buller, E. Trachsel, F. Bootz, Y. Zhang, L. Mannocci, SC Beck, M. Drumea-Mirancea, MW Seeliger, et al., Angew. Chem. They. Wheat. 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. VJ Gatto, GW 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, J. Apostolidis, F. Bruchertseifer, and A. Morgenstern, Solvent Extr. Ion Exch. 2007, 25, 339-349. 116. V. Radchenko, JW Engle, JJ Wilson, JR Maassen, FM Nortier, WA Taylor, ER Birnbaum, LA Hudston, KD John, ME Fassbender, J. Chromatogr. A 2015, 1380, 55-63. 117. MP Miranda-Hernandez, ER Valle-Gonzalez, D. Ferreira-Gomez, NO Perez, LF Flores-Ortiz, E. Medina-Rivero, Anal. Bioanal. Chem. 2016, 408, 1523-1530. 118. EW Price, KJ Edwards, KE Carnazza, SD Carlin, BM Zeglis, MJ Adam, C. Orvig, JS 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.

[0199] Several embodiments have been illustrated and described, and one of ordinary skill in the art, after reading the foregoing specification, may make modifications, equivalent substitutions, and other types of changes to the compounds of the present technology described herein or their salts, pharmaceutical compositions, derivatives, prodrugs, metabolites, tautomers, or racemic mixtures. Each of the foregoing aspects and embodiments may also include or incorporate such variations or aspects disclosed with respect to any or all of the other aspects and embodiments.

[0200] The present technology is not limited with respect to the specific embodiments described herein, which are intended as single illustrations of individual embodiments 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 will be apparent to those skilled in the art from the foregoing description, in addition to those recited herein. Such modifications and variations are intended to fall within the scope of the appended claims. It should be understood that the present technology is not limited to specific methods, reagents, compounds, compositions, labeled compounds, or biological systems, which of course may vary. It should also be understood that the terminology used herein is for the purpose of describing only specific embodiments, and is not intended to be limiting. It is therefore intended that the specification be considered as exemplary only, with the breadth, scope, and spirit of the present technology as indicated only by the appended claims, the definitions herein, and any equivalents thereof.

[0201] The embodiments illustratively described herein may suitably be practiced in the absence of any element or elements, or limitation or limitations not specifically disclosed herein. Thus, for example, the terms "comprising," "including," "containing," and the like, shall be read broadly and without limitation. Furthermore, the terms and expressions used herein are used for purposes of description and not for purposes of limitation, and no attempt is made 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. Furthermore, the phrase "consisting essentially of" is understood to include those elements specifically recited and additional elements that do not materially affect the basic and novel characteristics of the claimed technology. The phrase "consisting of" excludes any elements not specified.

[0202] Furthermore, when features or aspects of the disclosure are described in terms of a Markush group, one of skill in the art will recognize that the disclosure is also thereby described with respect to any individual member or subgroup of members of the Markush group. Each of the narrower species and subgeneric groupings falling within the general disclosure also form part of the invention. This includes the general description of the invention and is specifically recited herein, whether or not the material cut off, with conditions or negative limitations that exclude any subject from the genus.

[0203] As will be understood by those skilled in the art, for any and all purposes, particularly with respect to the written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of those subranges. Any recited range is fully described and can be easily recognized as being capable of dividing the same range into at least one half, one third, one quarter, one fifth, one tenth, etc. As a non-limiting example, each range discussed herein can be easily divided into a lower third, a middle third, and an upper third, etc. As will also be understood by those skilled in the art, all language, such as "up to," "at least," "greater than," "less than," etc., includes the recited number and subsequently means a range that can be divided into subranges as discussed above. Finally, as will be understood by those skilled in the art, a range includes each individual member.

[0204] All publications, patent applications, issued patents, and other documents (e.g., journals, articles, and / or textbooks) referenced herein are incorporated by reference herein 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 within the text that are incorporated by reference are excluded to the extent that they conflict with definitions in this disclosure.

[0205] The present technology may include, but is not limited to, the features and combinations of features recited in the following lettered paragraphs, it being understood that the following paragraphs are not to be construed as limiting the scope of the claims appended thereto, nor is it required that all such features be necessarily included in the scope of such claims. A. Formula I

[0206] [ka] [In the formula, M is an alpha-emitting radionuclide; A 1 is N or CR 1 and; A 2 is N or CR 2 and; A 3 is N or CR 3 and; A 4 is N or CR 4 and; A 5 is N or CR 5 and; A 6 is N or CR 6 and; A 7 is N or CR 7 and; A 8 is N or CR 8 and; A 9 is N or CR 9 and; A 10 is N or CR 10 where A 1 , A 2 , A 3 , A 4 , and A 5 Of these, 3 or less are N and A 6 , A 7 , A 8 , A 9 , and A 10 of which not more than three are N; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, halo, -OR', -(OCH2CH2) x-R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCHCH) y -OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', - selected from SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and an epoxide group, and optionally halo, -OR', -(OCH2CH2) x -R', -(OCH2CH2) y -OR', -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and the epoxide group are -(CH2) n - each independently linked to the carbon atom to which it is attached by a linker, where n is 1, 2, or 3; or directly adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 one or two pairs of groups are interconnected to form a 5- to 6-membered substituted or unsubstituted carbocyclic or nitrogen-containing ring; R' at each occurrence is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl, C2-C6 alkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl, or two R' groups attached to the same atom are interconnected to form a 3- to 6-membered ring; L 1 and L 2 are each independently -(CH2) p - where p is a value of 1, 2, or 3; r is 0 or 1; s is 0 or 1] or a pharma- ceutically acceptable salt thereof. B.A. 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , and A 10 The composition of paragraph A, wherein at least one of is N. C.A. 1 , A 2 , A 3 , A 4 , and A 5 At least one of is N, and A 6 , A 7 , A 8 , A 9 , and A 10 The composition of paragraph A or paragraph B, wherein at least one of is N. D.A. 1 , A 2 , A 3 , A 4 , and A 5 but not N. E.A. 6 , A 7 , A 8 , A 9 , and A 10 but not N. F. The composition of formula I is represented by formula Ia

[0207] [ka] or a pharma- ceutically acceptable salt thereof. G.R. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 The composition of any one of paragraphs A-F, wherein at least one of is a group selected from -C(O)R', -C(S)R', -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N3, -N=C=N-R', -SO2Cl, -C(O)Cl, and an epoxide group. H.R. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 At least one of the following is selected from the group consisting of halo, -OR', -(OCH2CH2) x -R', -(OCH2CH2) y The composition of any one of paragraphs A-F, wherein the group is selected from -OR', -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, and -CN. I. The composition of any one of paragraphs AH, wherein at least one of r and s is 1. J. The composition of any one of paragraphs A-J, wherein at least one of r and s is 0. K. The composition of formula I is represented by formula Ib

[0208] [ka] or a pharma- ceutically acceptable salt thereof. L.R. 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 The composition of any one of paragraphs A through K, wherein one or two pairs of immediately adjacent groups of the groups are interconnected to form a substituted or unsubstituted 4- to 6-membered carbocyclic or nitrogen-containing ring. M. The composition of formula I is represented by the formula Iv

[0209] [ka] [In the formula, R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, halo, -OR', -(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCHCH) y-OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', -SO 2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and an epoxide group, and optionally selected from the group consisting of halo, -OR', -(OCH2CH2) x -R', -(OCH2CH2) y -OR', -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and the epoxide group are -(CH2) n - each independently linked to the carbon atom to which it is attached by a linker, where n is 1, 2, or 3; The composition of any one of paragraphs A-C, G-J, and L, wherein R', for each occurrence, is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl, C2-C6 alkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl, or a pharma- ceutically acceptable salt thereof. N. The composition of formula I is represented by the formula Iw

[0210] [ka] [In the formula, R 11 , R 12 , R 13 , R 14 , R 17 , R 18 , R 19 , and R 20 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, halo, -OR', -(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCHCH) y -OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', -SO 2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and an epoxide group, and optionally selected from the group consisting of halo, -OR', -(OCH2CH2) x -R', -(OCH2CH2) y -OR', -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and the epoxide group are -(CH2) n - each independently linked to the carbon atom to which it is attached by a linker, where n is 1, 2, or 3; The composition of any one of paragraphs A-C, GJ, and L, wherein R', for each occurrence, is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl, C2-C6 alkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl, or a pharma- ceutically acceptable salt thereof. O. The composition comprises a compound of formula Ix

[0211] [ka] or a pharma- ceutically acceptable salt thereof. P.M. 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 + ), and uranium-230. Q. The composition comprises a compound of Formula II

[0212] [ka] [wherein M is an α-emitting radionuclide; A1 is N or CR 1 and; A 2 is N or CR 2 and; A 3 is N or CR 3 and; A 4 is N or CR 4 and; A 5 is N or CR 5 and; A 6 is N or CR 6 and; A 7 is N or CR 7 and; A 8 is N or CR 8 and; A 9 is N or CR 9 and; A 10 is N or CR 10 where A 1 , A 2 , A 3 , A 4 , and A 5 Of these, 3 or less are N and A 6 , A 7 , A 8 , A 9 , and A 10 of which not more than three are N; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 At least one of the groups is a selective cancer cell targeting group, or an alkylene, -O-, -(OCH2CH2) z- (wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -S-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)O-, -C(O)NR'-, -C(S)NR', ​​-NR'C(O)-, -NR'C(S)-, -NR'-, -NR'C(O)N-, -NR'C(S)N-, -S(O)-, -SO2-, -S(O)2O-, -SON2NR'-, -P(O)(OR')-, -P(O)(R')-, -C(NR')-, -OC(NR')-, -SC(NR')-, and optionally -O-, -(OCH2CH2) z -, -S-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)O-, -C(O)NR'-, -C(S)NR', ​​-NR'C(O)-, -NR'C(S)-, -NR'-, -NR'C(O)N-, -NR'C(S)N-, -S(O)-, -SO2-, -S(O)2O-, -SO2NR'-, -P(O)(OR')-, -P(O)(R')-, -C(NR')-, -OC(NR')-, -SC(NR')- are each independently linked to the carbon atom to which it is attached by a C1-C3 alkylene; Remaining R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, halo, -OR', -(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCHCH) y-OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', - selected from SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and an epoxide group, and optionally halo, -OR', -(OCH2CH2) x -R', -(OCH2CH2) y -OR', -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and the epoxide group are -(CH2) n - is each independently linked to the carbon atom to which it is attached by a linker, where n at each occurrence is independently 1, 2, or 3; or directly adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 one or two pairs of groups are interconnected to form a 5- to 6-membered substituted or unsubstituted carbocyclic or nitrogen-containing ring; R' at each occurrence is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl, C2-C6 alkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl, or two R' groups attached to the same atom are interconnected to form a 3- to 6-membered ring; L 1 and L 2 are each independently -(CH2) p - where p is a value of 1, 2, or 3; r is 0 or 1; and s is 0 or 1], or a pharma- ceutically acceptable salt thereof. R. The composition of paragraph Q, wherein said selective cancer cell targeting group contains amino acids linked by peptide bonds. S. The composition of Paragraph Q or Paragraph R, wherein said selective cancer cell targeting group is a cancer targeting antibody or antibody fragment. T. The composition of Paragraph Q or Paragraph R, wherein said selective cancer cell targeting group is an oligopeptide containing up to 50 amino acids. U. Formula II

[0213] [ka] [In the formula, M is an alpha-emitting radionuclide; A 1 is N or CR 1 and; A 2 is N or CR 2 and; A 3 is N or CR 3 and; A 4 is N or CR 4 and; A 5 is N or CR 5 and; A 6is N or CR 6 and; A 7 is N or CR 7 and; A 8 is N or CR 8 and; A 9 is N or CR 9 and; A 10 is N or CR 10 where A 1 , A 2 , A 3 , A 4 , and A 5 Of these, 3 or less are N and A 6 , A 7 , A 8 , A 9 , and A 10 of which not more than three are N; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 At least one of the groups is a selective cancer cell targeting group, or an alkylene, -O-, -(OCH2CH2) z a selective cancer cell targeting group linked to the carbon atom to which it is attached by -, -S-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)O-, -C(O)NR'-, -C(S)NR', ​​-NR'C(O)-, -NR'C(S)-, -NR'-, -NR'C(O)N-, -NR'C(S)N-, -S(O)-, -SO2-, -S(O)2O-, -SO2NR'-, -P(O)(OR')-, -P(O)(R')-, -C(NR')-, -OC(NR')-, -SC(NR')-, and optionally -O-, -(OCH2CH2) z-, -S-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)O-, -C(O)NR'-, -C(S)NR', ​​-NR'C(O)-, -NR'C(S)-, -NR'-, -NR'C(O)N-, -NR'C(S)N-, -S(O)-, -SO2-, -S(O)2O-, -SO2NR'-, -P(O)(OR')-, -P(O)(R')-, -C(NR')-, -OC(NR')-, -SC(NR')- are each independently linked to the carbon atom to which it is attached by a C1-C3 alkylene; Remaining R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, halo, -OR', -(OCH2CH2) x -R' (wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -(OCHCH) y -OR' (wherein y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', - selected from SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and an epoxide group, and optionally halo, -OR', -(OCH2CH2) x -R', -(OCH2CH2) y-OR', -SR', -OC(O)R', -C(O)OR', -C(S)OR', -C(O)NR'R', -C(S)NR'R', -NR'C(O)R', -NR'C(S)R', -NR'R', -NR'C(O)NR', ​​-NR'C(S)NR', ​​-S(O)R', -SOR', -SO2R', -SO2(OR'), -SO2NR'2, -P(O)(OR')2, -P(O)R'(OR'), -P(O)R'2, -NO2, -CN, -OCN, -SCN, -NCO, -NCS, -NR'-NR'R', -N, -N=C=N-R', -SO2Cl, -C(O)Cl, and the epoxide group are -(CH2) n - each independently linked to the carbon atom to which it is attached by a linker, where n is 1, 2, or 3; Or, the directly adjacent R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 one or two pairs of groups are interconnected to form a 5- to 6-membered substituted or unsubstituted carbocyclic or nitrogen-containing ring; R' at each occurrence is independently H, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C6 cycloalkenyl, C2-C6 alkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl, or two R' groups attached to the same atom are interconnected to form a 3- to 6-membered ring; L 1 and L 2 are each independently -(CH2) p - where p is a value of 1, 2, or 3; r is 0 or 1; and s is 0 or 1] or a pharma- ceutically acceptable salt thereof to a subject having cancer. V. The method of paragraph U, wherein said selective cancer cell targeting group contains amino acids linked by peptide bonds. W. The method of paragraph U or paragraph V, wherein said selective cancer cell targeting group is a cancer targeting antibody or antibody fragment. X. The method of paragraph U or paragraph V, wherein said selective cancer cell targeting group is an oligopeptide containing up to 50 amino acids. Y.M. 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 + ), and uranium-230. Z. A composition comprising a pharma- ceutically acceptable carrier and the composition of any one of paragraphs A-T.

[0214] Other embodiments are set forth in the following claims, along with the full scope of equivalents to which such claims are entitled.

Claims

1. Formula Ib 【Chemistry 1】 wherein M is an α-emitting radionuclide; R ２ and R ７ are each —C(O)OR′, R ９ are -C(O)R', -C(S)R', -OCN, -SCN, -NCO, -NR'R', -NCS, -NR'-NR'R', -N ３ , -N=C=NR', -SO ２ is a group selected from Cl, —C(O)Cl, and an epoxide group; R ３ , R ４ , R ５ , R ８ and R １０ are H, R' at each occurrence is independently H; L １ and L ２ Each independently represents -(CH ２ ) ｐ - (wherein p is 1); r is 1; and s is 1; or a pharma- ceutically acceptable salt thereof.

2. R ９ is -NCS or -NH ２ 2. The composition of claim 1 ,

3. M is actinium-225 ( ２２５ A.C. 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 ＋ 3. The composition of claim 1, wherein the uranium-230 is selected from the group consisting of uranium-230, uranium-240, and uranium-250.

4. Formula Ib 【Chemistry 2】 wherein M is an α-emitting radionuclide; R ９ is an alkylene, -O-, -(OCH ２ CH ２ ) ｚ -(wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), -S-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)O-, -C(O)NR'-, -C(S)NR', ​​-NR'C(O)-, -NR'C(S)-, -NR'-, -NR'C(O)N-, -NR'C(S)N-, -S(O)-, -SO ２ -, -S(O) ２ O-, -SO ２ A cancer targeting antibody that is attached to a carbon atom of a pyridine ring via -NR'-, -P(O)(OR')-, -P(O)(R')-, -C(NR')-, -OC(NR')-, -SC(NR')-, and optionally -O-, -(OCH ２ CH ２ ) ｚ -, -S-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)O-, -C(O)NR'-, -C(S)NR', ​​-NR'C(O)-, -NR'C(S)-, -NR'-, -NR'C(O)N-, -NR'C(S)N-, -S(O)-, -SO ２ -, -S(O) ２ O-, -SO ２ NR'-, -P(O)(OR')-, -P(O)(R')-, -C(NR')-, -OC(NR')-, -SC(NR')- are C １ ~C ３ each independently bonded to a carbon atom of the pyridine ring via an alkylene; R ２ and R ７ are each —C(O)OR′, R ３ , R ４ , R ５ , R ８ and R １０ are H, R' at each occurrence is independently H; L １ and L ２ Each independently represents -(CH ２ ) ｐ - (wherein p is 1); r is 1; and s is 1], or a pharma- ceutically acceptable salt of said compound, for use in targeted radiotherapy of cancer.

5. M is actinium-225 ( ２２５ A.C. 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 ＋ 5. The composition of claim 4, wherein the uranium-230 is selected from the group consisting of uranium-230, uranium-240, and uranium-250.

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