WO2022251516A2 - Complexes à chélateurs acycliques et leur utilisation en radiothérapie ciblée de cancer - Google Patents

Complexes à chélateurs acycliques et leur utilisation en radiothérapie ciblée de cancer Download PDF

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WO2022251516A2
WO2022251516A2 PCT/US2022/031157 US2022031157W WO2022251516A2 WO 2022251516 A2 WO2022251516 A2 WO 2022251516A2 US 2022031157 W US2022031157 W US 2022031157W WO 2022251516 A2 WO2022251516 A2 WO 2022251516A2
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compound
formula
pharmaceutically acceptable
solvate
acceptable salt
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WO2022251516A3 (fr
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Justin J. Wilson
Joshua J. WOODS
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Cornell University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C07D215/30—Metal salts; Chelates

Definitions

  • a compound of Formula (I) is provided: or a pharmaceutically acceptable salt and/or solvate thereof, wherein Z 1 is R 5 , and Z 2 is R 6 ; or Z 1 and Z 2 taken together are a C 4 alkylene group optionally substituted by R 9 ; Z 3 is R 7 , and Z 4 is C(O); or Z 3 and Z 4 taken together with the carbon atoms to which they are bound are a 6-membered aryl ring optionally substituted by R 10 ; Z 5 is R 8 , and Z 6 is C(O); or Z 5 and Z 6 are taken together with the carbon atoms to which they are bound are a 6-membered aryl ring optionally substituted by R 11 ; R 1 , R 2 , R 3
  • a compound of Formula (II) is provided or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is 230 U, 67 Ga, 68 Ga, 64 Cu, or 111 In, optionally where M 1 is 230 UO 2 2+ , 230 U 6+ , 67 Ga 3+ , 6 8 Ga 3+ , 64 Cu 2+ , or 111 In 3+ ; Z 1 is R 5 , and Z 2 is R 6 ; or Z 1 and Z 2 taken together are a C4 alkylene group optionally substituted by R 9 ; Z 3 is R 7 , and Z 4 is C(O); or Z 3 and Z 4 taken together with the carbon atoms to which they are bound are a 6-membered aryl ring optionally substituted by R 10 ; Z 5 is R 8 , and Z 6 is C(O); or Z 5 and Z 6 are taken together with the carbon atoms to which they are bound are a 6-membered aryl ring
  • the present technology provides a compound (e.g., a “targeting compound”) useful in targeted radiotherapy of cancer and/or mammalian tissue overexpressing, e.g., an antigen or a receptor, where the compound is of Formula (III) or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is 230 UO 2 , 67 Ga, 68 Ga, 64 Cu, or 111 In, optionally where M 1 is 230 UO 2 2+ , 230 U 6+ , 67 Ga 3+ , 6 8 Ga 3+ , 64 Cu 2+ , or 111 In 3+ ; Z 1 is H or –L 5 –R 25 , and Z 2 is H or –L 6 –R 26 ; or Z 1 and Z 2 taken together are a C 4 alkylene group optionally substituted by R 9 ; Z 3 is H or –L 7 –R 27 , and Z 4 is C(O); or Z 3 and Z 4 taken together with the
  • a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (I) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide.
  • a modified antibody, modified antibody fragment, or modified binding peptide is provided that includes a linkage arising from conjugation of a compound of Formula (II) or a pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide.
  • the antibody includes Codrituzumab (GC33), belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizum
  • the antibody fragment includes an antigen-binding fragment of Codrituzumab (GC33), belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalu
  • the binding peptide includes a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment thereof.
  • PSMA prostate specific membrane antigen
  • the present technology also provides compositions (e.g., pharmaceutical compositions) and medicaments comprising any of one of the embodiments of the compounds of Formulas (I), (II), or (III) (or a pharmaceutically acceptable salt and/or solvate thereof) disclosed herein and a pharmaceutically acceptable carrier or one or more excipients or fillers.
  • compositions e.g., pharmaceutical compositions
  • medicaments comprising any of one of the embodiments of the therapeutic radiopharmaceutical agents comprising chelators (e.g., compounds of Formula (I)) and radionuclides disclosed herein and a pharmaceutically acceptable carrier or one or more excipients or fillers.
  • compositions e.g., pharmaceutical compositions
  • medicaments comprising any of one of the embodiments of the modified antibody, modified antibody fragment, or modified binding peptide of the present technology disclosed herein and a pharmaceutically acceptable carrier or one or more excipients or fillers.
  • a method of treating a subject includes administering a targeting compound of the present technology to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of the present technology to the subject.
  • the subject suffers from cancer and/or mammalian tissue overexpressing, e.g., an antigen or a receptor.
  • a compound is provided that includes a first domain having a blood- protein binding moiety with low specific affinity for the blood-protein, a second domain having a tumor targeting moiety with high affinity for a tumor antigen, and a third domain having a chelator.
  • FIGs.1A-1H show X-ray crystal structures of the [UO 2 (L)] complexes.
  • FIGs.1A and 1B show X-ray crystal structures of [UO 2 (dedpa)] (FIG.1A, top view; FIG.1B, side view).
  • FIGs.1C and 1D show X-ray crystal structures of [UO 2 (CHXdedpa)] (FIG.1C, top view; FIG. 1D, side view).
  • FIGs.1E and 1F show X-ray crystal structures of [UO 2 (hox)] (FIG.1E, top view; FIG.1F, side view).
  • FIGs.1G and 1H show X-ray crystal structures of [UO 2 (CHXhox)](NO 3 ) (FIG.1G, top view; FIG.1H, side view). Thermal ellipsoids are drawn at the 50% probability level. Counterions, outer-sphere solvent molecules, and hydrogen atoms bound to carbon atoms are omitted for clarity. For [UO 2 (CHXdedpa)], only one of the two independent molecules present in the asymmetric unit is shown.
  • FIGs.2A and 2B show the kinetic stability of [UO 2 (L)] complexes ([UO 2 (dedpa)], [UO 2 (CHXdedpa)], [UO 2 (hox)], and [UO 2 (CHXhox)], respectively) in 0.1 M TRIS buffer (pH 7.4, 37 °C) containing 2000 eq. HAP (FIG.2A) or human plasma (FIG.2B) over 14 d as measured by HPLC.
  • FIGs.3A-3D show the ex vivo biodistribution profiles of [UO 2 (NO 3 )] ⁇ 6H 2 O (FIG.3A), [UO 2 (dedpa)] (FIG.3B), [UO 2 (CHXdedpa)] (FIG.3C), and [UO 2 (hox)] (FIG.3D) at 30 min, 2 h and 24 h.
  • FIGs.3E-3F show comparison of the uranium content in the tibia (FIG.3E) and lung (FIG.3F) for the data shown in FIGs.3A-3D.
  • an R group is defined to include hydrogen or H, it also includes deuterium and tritium.
  • Compounds comprising radioisotopes such as tritium, C 14 , P 32 and S 35 are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein.
  • substituted refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non-hydrogen or non-carbon atoms.
  • Substituted groups 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.
  • a substituted group is substituted with one or more substituents, unless otherwise specified.
  • a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents.
  • substituent groups include: halogens (i.e., F, Cl, Br, and I); hydroxyls; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxylates; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; pentafluorosulfanyl (i.e., SF 5 ), sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothi
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.
  • C m -C n such as C 1 -C 12 , C 1 -C 8 , or C 1 -C 6 when used before a group refers to that group containing m to n carbon atoms.
  • Alkyl groups include straight chain and branched chain alkyl groups having from 1 to 12 carbon atoms, and typically from 1 to 10 carbons or, in some embodiments, from 1 to 8, 1 to 6, or 1 to 4 carbon atoms.
  • straight chain alkyl groups include groups such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • 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 may be substituted or unsubstituted.
  • substituted alkyl groups may be substituted one or more times with substituents such as those listed above, and include without limitation haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, carboxyalkyl, and the like.
  • Cycloalkyl groups include mono-, bi- or tricyclic alkyl groups having from 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 not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7.
  • Bi- and tricyclic ring systems include both 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 may be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups, which may be substituted with substituents such as those listed above.
  • Cycloalkylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • cycloalkylalkyl groups have from 4 to 16 carbon atoms, 4 to 12 carbon atoms, and typically 4 to 10 carbon atoms.
  • Cycloalkylalkyl groups may be substituted or unsubstituted. Substituted cycloalkylalkyl groups may be substituted at the alkyl, the cycloalkyl or both the alkyl and cycloalkyl portions of the group.
  • Alkenyl groups include straight and branched chain alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Alkenyl groups have from 2 to 12 carbon atoms, and typically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. In some embodiments, the alkenyl group has one, two, or three carbon-carbon double bonds.
  • Alkenyl groups may be substituted or unsubstituted.
  • Representative substituted alkenyl groups may be mono-substituted or substituted more than once, such as, but not limited to, mono-, di- or tri-substituted with substituents such as those listed above.
  • Cycloalkenyl groups include cycloalkyl groups as defined above, having at least one double bond between two carbon atoms.
  • Cycloalkenyl groups may be substituted or unsubstituted. In some embodiments the cycloalkenyl group may have one, two or three double bonds but does not include aromatic compounds. Cycloalkenyl groups have from 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.
  • Cycloalkenylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above. Cycloalkenylalkyl groups may be substituted or unsubstituted. Substituted cycloalkenylalkyl groups may be substituted at the alkyl, the cycloalkenyl or both the alkyl and cycloalkenyl portions of the group. Representative substituted cycloalkenylalkyl groups may be substituted one or more times with substituents such as those listed above.
  • Alkynyl groups include straight and branched chain alkyl groups as defined above, except that at least one triple bond exists between two carbon atoms.
  • Alkynyl groups have from 2 to 12 carbon atoms, and typically from 2 to 10 carbons or, in some embodiments, from 2 to 8, 2 to 6, or 2 to 4 carbon atoms.
  • the alkynyl group has one, two, or three carbon-carbon triple bonds. Examples include, but are not limited to – C ⁇ CH, -C ⁇ CCH 3 , -CH 2 C ⁇ CCH 3 , -C ⁇ CCH 2 CH(CH 2 CH 3 ) 2 , among others.
  • Alkynyl groups may be substituted or unsubstituted.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • Aryl groups herein include monocyclic, bicyclic and tricyclic ring systems.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups.
  • aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups.
  • the aryl groups are phenyl or naphthyl.
  • Aryl groups may be substituted or unsubstituted.
  • aryl groups includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like). Representative substituted aryl groups may be mono- substituted or substituted more than once.
  • monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.
  • Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • aralkyl groups contain 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms.
  • Aralkyl groups may be substituted or unsubstituted.
  • Substituted aralkyl groups may be substituted at the alkyl, the aryl or both the 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 listed above.
  • Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non-aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S.
  • the heterocyclyl group contains 1, 2, 3 or 4 heteroatoms.
  • heterocyclyl groups include mono-, bi- and tricyclic rings having 3 to 16 ring members, whereas other such groups have 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, for example, imidazolyl, imidazolinyl and imidazolidinyl groups.
  • heterocyclyl group includes fused ring species including those comprising fused aromatic and non-aromatic groups, such as, for example, benzotriazolyl, 2,3- dihydrobenzo[1,4]dioxinyl, and benzo[1,3]dioxolyl.
  • the phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups may 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,
  • substituted heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with various substituents such as those listed above.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
  • Heteroaryl groups include, but are not limited to, groups such as 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,
  • Heteroaryl groups include fused ring compounds in which all rings are aromatic such as indolyl groups and include fused ring compounds in which only one of the rings is aromatic, such as 2,3-dihydro indolyl groups. Heteroaryl groups may be substituted or unsubstituted. Thus, the phrase “heteroaryl groups” includes fused ring compounds as well as includes heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above.
  • Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heterocyclyl group as defined above. Heterocyclylalkyl groups may be substituted or unsubstituted. Substituted heterocyclylalkyl groups may be substituted at the alkyl, the heterocyclyl or both the alkyl and heterocyclyl portions of the group.
  • heterocyclyl alkyl 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 listed above.
  • Heteroaralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above. Heteroaralkyl groups may be substituted or unsubstituted.
  • Substituted heteroaralkyl groups may be substituted at the alkyl, the heteroaryl or both the alkyl and heteroaryl portions of the group.
  • Representative substituted heteroaralkyl groups may be substituted one or more times with substituents such as those listed above.
  • Groups described herein having two or more points of attachment i.e., divalent, trivalent, or polyvalent
  • divalent alkyl groups are alkylene groups
  • divalent aryl groups are arylene groups
  • divalent heteroaryl groups are divalent heteroarylene groups, and so forth.
  • Substituted groups having a single point of attachment to the compound of the present technology are not referred to using the “ene” designation.
  • chloroethyl is not referred to herein as chloroethylene.
  • Such groups may further be substituted or unsubstituted.
  • Alkoxy groups are hydroxyl groups (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group as defined above.
  • Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, 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.
  • Alkoxy groups may be substituted or unsubstituted. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.
  • alkanoyl and alkanoyloxy can refer, respectively, to – C(O)–alkyl and –O–C(O)–alkyl groups, where in some embodiments the alkanoyl or alkanoyloxy groups each contain 2–5 carbon atoms.
  • aryloyl and aryloyloxy respectively refer to –C(O)–aryl and –O–C(O)–aryl groups.
  • aryloxy and arylalkoxy refer to, respectively, a substituted or unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to the oxygen atom at the alkyl. 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 listed above. [0040]
  • carboxylic acid as used herein refers to a compound with a –C(O)OH group.
  • carboxylate refers to a –C(O)O – group.
  • a “protected carboxylate” refers to a –C(O)O-G where G is a carboxylate protecting group.
  • Carboxylate protecting groups are well known to one of ordinary skill in the art. An extensive list of protecting groups for the carboxylate group functionality may be found in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999) which can be added or removed using the procedures set forth therein and which is hereby incorporated by reference in its entirety and for any and all purposes as if fully set forth herein.
  • esters refers to –COOR 70 groups.
  • R 70 is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
  • amide (or “amido”) includes C- and N-amide groups, i.e., -C(O)NR 71 R 72 , and –NR 71 C(O)R 72 groups, respectively.
  • 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.
  • Amido groups therefore include but are not limited to carbamoyl groups (-C(O)NH 2 ) and formamide groups (-NHC(O)H).
  • the amide is –NR 71 C(O)-(C 1-5 alkyl) and the group is termed "carbonylamino,” and in others the amide is –NHC(O)-alkyl and the group is termed "alkanoylamino.”
  • the term “nitrile” or “cyano” as used herein refers to the –CN group.
  • Urethane groups include N- and O-urethane groups, i.e., -NR 73 C(O)OR 74 and -OC(O)NR 73 R 74 groups, respectively.
  • R 73 and R 74 are independently a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • R 73 may also be H.
  • amine or “amino” as used herein refers to –NR 75 R 76 groups, 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.
  • the amine is alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH 2 , methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.
  • sulfonamido includes S- and N-sulfonamide groups, i.e., -SO 2 NR 78 R 79 and –NR 78 SO 2 R 79 groups, respectively.
  • R 78 and R 79 are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl, or heterocyclyl group as defined herein.
  • Sulfonamido groups therefore include but are not limited to sulfamoyl groups (-SO 2 NH 2 ).
  • the sulfonamido is –NHSO 2 -alkyl and is referred to as the "alkylsulfonylamino" group.
  • thiol refers to —SH groups
  • sulfides include —SR 80 groups
  • sulfoxides include —S(O)R 81 groups
  • sulfones include -SO 2 R 82 groups
  • sulfonyls include —SO 2 OR 83 .
  • 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.
  • the sulfide is an alkylthio group, -S-alkyl.
  • urea refers to –NR 84 -C(O)-NR 85 R 86 groups.
  • R 84 , R 85 , and R 86 groups are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclyl, or heterocyclylalkyl group as defined herein.
  • amidine refers to –C(NR 87 )NR 88 R 89 and –NR 87 C(NR 88 )R 89 , wherein R 87 , R 88 , and R 89 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • guanidine refers to –NR 90 C(NR 91 )NR 92 R 93 , wherein R 90 , R 91 , R 92 and R 93 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • halogen or “halo” as used herein refers to bromine, chlorine, fluorine, or iodine.
  • the halogen is fluorine. In other embodiments, the halogen is chlorine or bromine.
  • hydroxyl as used herein can refer to –OH or its ionized form, –O – .
  • the term “imide” refers to –C(O)NR 98 C(O)R 99 , wherein R 98 and R 99 are each independently hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
  • the term “imine” refers to –CR 100 (NR 101 ) and –N(CR 100 R 101 ) groups, wherein R 100 and R 101 are each independently hydrogen or a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein, with the proviso that R 100 and R 101 are not both simultaneously hydrogen.
  • nitro as used herein refers to an –NO 2 group.
  • the term “trifluoromethyl” as used herein refers to –CF 3 .
  • trifluoromethoxy refers to –OCF 3 .
  • zido refers to –N 3 .
  • trifluoromethyldiazirido refers to [0062]
  • isocyano refers to –NC.
  • isothiocyano refers to –NCS.
  • salts of compounds described herein are within the scope of the present technology and include acid or base addition salts which retain the desired pharmacological activity and is not biologically undesirable (e.g., the salt is not unduly toxic, allergenic, or irritating, and is bioavailable).
  • pharmaceutically acceptable salts can be formed with inorganic acids (such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid), organic acids (e.g., alginate, 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, naphthalene sulfonic acid, and p-toluenesulfonic acid) or acidic amino acids (such as aspartic acid and glutamic acid).
  • inorganic acids such as hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid
  • organic acids e.g., alginate, formic acid, acetic acid, benzoic acid, gluconic acid, fumaric acid, ox
  • the compound of the present technology when it has an acidic group, such as for example, a carboxylic acid group, it can form salts with metals, such as alkali and earth alkali metals (e.g., Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+ ), ammonia or organic amines (e.g. dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine) or basic amino acids (e.g., arginine, lysine and ornithine).
  • alkali and earth alkali metals e.g., Na + , Li + , K + , Ca 2+ , Mg 2+ , Zn 2+
  • ammonia or organic amines e.g. dicyclohexylamine, trimethylamine, triethylamine, pyridine, picoline, ethanolamine,
  • Such salts can be prepared in situ during isolation and purification of the compounds or by separately reacting the purified compound in its free base or free acid form with a suitable acid or base, respectively, and isolating the salt thus formed.
  • Those of skill in the art will appreciate that compounds of the present technology may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism and/or stereoisomerism.
  • Tautomers refers to isomeric forms of a compound that are in equilibrium with each other. The presence and concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution.
  • quinazolinones may exhibit the following isomeric forms, which are referred to as tautomers of each other: .
  • guanidines may exhibit the following isomeric forms in protic organic solution, also referred to as tautomers of each other: .
  • Stereoisomers of compounds also known as optical isomers
  • compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.
  • the compounds of the present technology may exist as solvates, especially hydrates. Hydrates may form during manufacture of the compounds or compositions comprising the compounds, or hydrates may form over time due to the hygroscopic nature of the compounds.
  • Alpha-emitting radionuclides are of much higher energy, and thus substantially more potent, than beta-emitting radionuclides. Additionally, the radionuclide 230 U possesses a 20.8-day half-life, and thus can be suitable for use with the long biological circulation time of antibody-based targeting vectors.
  • At least one of R 1 , R 2 , R 3 , R 4 , Z 1 , Z 2 , Z 3 , or Z 5 in Formula (I) is not H. In any embodiment herein, it may be that one of R 1 , R 2 , R 3 , R 4 , Z 1 , Z 2 , Z 3 , or Z 5 in Formula (I) is not H and the remainder are H.
  • the compounds of the invention may have one or more chiral centers.
  • certain uncomplexed form of Formula (I) can be complexed with a radionuclide, such as an alpha-emitting radionuclide, at room temperature (e.g., 18-30°C, or about or no more than 20°C, 25°C, or 30°C) at high radiochemical yields, e.g., at least or greater than 90%, 95%, 97%, or 98%.
  • a radionuclide such as an alpha-emitting radionuclide
  • a compound of Formula (II) is provided or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is 230 U, 67 Ga, 68 Ga, 64 Cu, or 111 In; Z 1 is R 5 , and Z 2 is R 6 ; or Z 1 and Z 2 taken together are a C 4 alkylene group optionally substituted by R 9 ; Z 3 is R 7 , and Z 4 is C(O); or Z 3 and Z 4 taken together with the carbon atoms to which they are bound are a 6-membered aryl ring optionally substituted by R 10 ; Z 5 is R 8 , and Z 6 is C(O); or Z 5 and Z 6 are taken together with the carbon atoms to which they are bound are a 6-membered aryl ring optionally substituted by R 11 ; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently H, OH, NH
  • M 1 is uranium-230 ( 230 UO 2 2+ or 230 U 6+ ), gallium-67 ( 67 Ga 3+ ), gallium-68 ( 68 Ga 3+ ), copper-64 ( 64 Cu 2+ ), or Indium-111 ( 111 In 3+ ).
  • the present technology provides a compound (e.g., a “targeting compound”) useful in targeted radiotherapies, for example, targeted radiotherapy of cancer and/or mammalian tissue overexpressing e.g., an antigen or a receptor, where the compound is of Formula (III) or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is 230 U, 67 Ga, 68 Ga, 64 Cu, or 111 In; Z 1 is H or –L 5 –R 25 , and Z 2 is H or –L 6 –R 26 ; or Z 1 and Z 2 taken together are a C4 alkylene group optionally substituted by R 9 ; Z 3 is H or –L 7 –R 27 , and Z 4 is C(O); or Z 3 and Z 4 taken together with the carbon atoms to which they are bound are a 6-membered aryl ring optionally substituted by R 10 ; Z 5 is H or –L 8 –R 28 , and
  • M 1 is uranium-230 ( 230 UO 2 2+ or 230 U 6+ ), gallium-67 ( 67 Ga 3+ ), gallium-68 ( 68 Ga 3+ ), copper-64 ( 64 Cu 2+ ), or Indium-111 ( 111 In 3+ ).
  • Representative R 21 , R 25 , R 26 , R 27 , and R 28 groups include those antibodies listed in Table A as well as antigen-binding fragments of such antibodies and any equivalent embodiments, as would be known to those of ordinary skill in the art. Belimumab 7138501 1 g 2 Also designated Ch14.18.
  • the binding peptide comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment thereof.
  • PSMA prostate specific membrane antigen
  • PSMA binding peptides include, but are not limited to, those according to the following structure where nn is 0, 1, or 2, and P 1 , P 2 , and P 3 are each independently H, methyl, benzyl, 4- methoxybenzyl, or tert-butyl. In any embodiment herein, it may be that each of P 1 , P 2 , and P 3 are H.
  • Somatostatin illustrated in Scheme A, is a peptide hormone that regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones. Somatostatin has two active forms produced by alternative cleavage of a single preproprotein.
  • somatostatin receptors There are five known somatostatin receptors, all being G protein-coupled seven transmembrane receptors: SST1 (SSTR1); SST2 (SSTR2); SST3 (SSTR3); SST4 (SSTR4); and SST5 (SSTR5).
  • Exemplary somatostatin receptor agonists include somatostatin itself, lanreotide, octreotate, octreotide, pasireotide, and vapreotide.
  • Octreotide is an octapeptide that mimics natural somatostatin but has a significantly longer half-life in vivo.
  • Octreotide is used for the treatment of growth hormone producing tumors (acromegaly and gigantism), when surgery is contraindicated, pituitary tumors that secrete thyroid stimulating hormone (thyrotropinoma), diarrhea and flushing episodes associated with carcinoid syndrome, and diarrhea in people with vasoactive intestinal peptide-secreting tumors (VIPomas).
  • Lanreotide is used in the management of acromegaly and symptoms caused by neuroendocrine tumors, most notably carcinoid syndrome.
  • Pasireotide is a somatostatin analog with an increased affinity to SSTR5 compared to other somatostatin agonists and is approved for treatment of Cushing's disease and acromegaly. Vapreotide is is used in the treatment of esophageal variceal bleeding in patients with cirrhotic liver disease and AIDS-related diarrhea.
  • Bombesin is a peptide originally isolated from the skin of the European fire-bellied toad (Bombina bombina). In addition to stimulating gastrin release from G cells, bombesin activates at least three different G-protein-coupled receptors: BBR1, BBR2, and BBR3, where such activity includes agonism of such receptors in the brain.
  • Bombesin is also a tumor marker for small cell carcinoma of lung, gastric cancer, pancreatic cancer, and neuroblastoma.
  • Bombesin receptor agonists include, but are not limited to, BBR-1 agonists, BBR-2 agonists, and BBR-3 agonists.
  • Seprase or Fibroblast Activation Protein (FAP) is an integral membrane serine peptidase. In addition to gelatinase activity, seprase has a dual function in tumour progression. Seprase promotes cell invasiveness towards the ECM and also supports tumour growth and proliferation. Seprase binding compounds include seprase inhibitors.
  • Glypican-3 is a cell-surface glycoprotein consisting of heparan sulfate glycosaminoglycan chains and an inner protein core. Glypican-3 immunostaining has utility for differentiating hepatocellular carcinoma (HCC) (see, e.g., Filmus J, Capurro M (2004). "Glypican-3 and alphafetoprotein as diagnostic tests for hepatocellular carcinoma”. Molecular Diagnosis.8 (4): 207–212) and dysplastic changes in cirrhotic livers; HCC stains with glypican 3, while liver with dysplastic changes and/or cirrhotic changes does not.
  • HCC hepatocellular carcinoma
  • GPC3 protein expression has been found in HCC, not in normal liver and cholangiocarcinoma. GPC3 is also expressed to a lesser degree in melanoma, ovarian clear-cell carcinomas, yolk sac tumors, neuroblastoma, hepatoblastoma, Wilms' tumor cells, and other tumors. GPC3 is a promising therapeutic target for treating liver cancer (see, e.g., Ishiguro T, Sugimoto M, Kinoshita Y, Miyazaki Y, Nakano K, Tsunoda H, et al. "Anti-glypican 3 antibody as a potential antitumor agent for human liver cancer". Cancer Research.68 (23): 9832–9838).
  • a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (I) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide.
  • a modified antibody, modified antibody fragment, or modified binding peptide is provided that includes a linkage arising from conjugation of a compound of Formula (II) or a pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide.
  • the antibody includes belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendetide, Elotuzumab,
  • the antibody fragment includes an antigen-binding fragment of belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelumab, Durvalumab, Capromab pendet
  • the binding peptide includes a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment thereof.
  • PSMA prostate specific membrane antigen
  • the binding peptide includes Codrituzumab (GC33) or a binding fragment thereof.
  • modified antibody, modified antibody fragment, or modified binding peptide of the present technology it may be that the linkage arises from conjugation of the compound with the antibody, antibody fragment, or binding peptide; and wherein the compound is a compound of Formula (I) (e.g., a compound of Formula (I-A), (I-B1), (I-B2), (I- C1), (I-C2), (I-D1), (I-D2), or (I-D3)), or pharmaceutically acceptable salt and/or solvate thereof.
  • a compound of Formula (I) e.g., a compound of Formula (I-A), (I-B1), (I-B2), (I- C1), (I-C2), (I-D1), (I-D2), or (I-D3)
  • pharmaceutically acceptable salt and/or solvate thereof e.g., a compound of Formula (I-A), (I-B1), (I-B2), (I- C1), (I-C2), (I
  • a modified antibody, modified antibody fragment, or modified binding peptide of the present technology it may be that the linkage arises from conjugation of the compound with the antibody, antibody fragment, or binding peptide; and wherein the compound is a compound of Formula (II) (e.g., a compound of Formula (II-A), (II-B1), (II-B2), (II-C1), (II-C2), (II-D1), (II-D2), or (II-D3)), or pharmaceutically acceptable salt and/or solvate thereof.
  • a compound of Formula (II) e.g., a compound of Formula (II-A), (II-B1), (II-B2), (II-C1), (II-C2), (II-D1), (II-D2), or (II-D3)
  • pharmaceutically acceptable salt and/or solvate thereof e.g., a compound of Formula (II-A), (II-B
  • the structures include compounds of Formula (I-A) (e.g., compounds of Formula (I-A*) or (I-A**)); a therapeutic radiopharmaceutical agent comprising a compound of Formula (I-A) or pharmaceutically acceptable salt and/or solvate thereof and a radionuclide; a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (I-A) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide; compounds of Formula (II-A) (e.g., compounds of Formula (II-A*) or (II- A**)); a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (II-A) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide; and targeting compounds of
  • a compound of Formula (II-A) is a compound of Formula (II- A*) or Formula (II-A**)
  • a compound of Formula (III-A) is a compound of Formula (III- A*) or Formula (III-A**)
  • a therapeutic radiopharmaceutical agent described herein comprises a compound and a radionuclide, where the compound is , or a pharmaceutically acceptable salt and/or solvate thereof.
  • a compound of Formula (II-A) is or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is a radionuclide.
  • M 1 is a radionuclide.
  • a modified antibody, modified antibody fragment, or modified binding peptide of the present technology it may be that the modified antibody, modified antibody fragment, or modified binding peptide comprises a moiety having the following structure wherein one of the hydrogens is being substituted by a linkage or a pharmaceutically acceptable salt and/or solvate thereof.
  • Targeting compounds of Formula (III-A) may be prepared by a process that includes reacting a compound of Formula (I-A) or (II-A) with R 21 -R 1a , where Table B provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).
  • R 21 may be conjugated to moiety R 41 by reaction of complementary chemical functional groups R 1a and R 1 (e.g., represented by –X 1 -W 1 in Table B) to form linker L 1 (e.g., represented by –X 1 -LL 1 in Table B).
  • R 1a and R 1 e.g., represented by –X 1 -W 1 in Table B
  • linker L 1 e.g., represented by –X 1 -LL 1 in Table B.
  • R 21 -R 1a may include a modified target amino acid residue within a protein (e.g., a target amino acid residue described herein such as one of the representative antibodies disclosed in Table A or an antigen-binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment of any one thereof; or an antibody codrituzumab (GC33), or a binding fragment of any one thereof).
  • a target amino acid residue described herein such as one of the representative antibodies disclosed in Table A or an antigen-binding fragment thereof
  • a PSMA binding peptide e.g., a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment of any one thereof
  • GC33 antibody codrituzumab
  • R 1a may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table B, where R 1 (e.g., represented by –X 1 -W 1 in Table B) may be selected to selectively react with R 1a in order to provide L 1 (e.g., represented by –X 1 -LL 1 in Table B) of Formula (III-A).
  • R 1 e.g., represented by –X 1 -W 1 in Table B
  • L 1 e.g., represented by –X 1 -LL 1 in Table B
  • the structures include compounds of Formula (I-B1) (e.g., compounds of Formula (I-B1*) or Formula (I-B1**)); a therapeutic radiopharmaceutical agent comprising a compound of Formula (I-B1) or pharmaceutically acceptable salt and/or solvate thereof and a radionuclide; a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (I-B1) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide; compounds of Formula (II-B1) (e.g., compounds of Formula (II-B1*) or Formula (II-B1**)), a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (II-B1) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide;
  • a compound of Formula (I-B1) is a compound of Formula (I- B1*) or Formula (I-B1**) [0106] In some embodiments, a compound of Formula (II-B1) is a compound of Formula (II- B1*) or Formula (II-B1**) [0107] In some embodiments, a compound of Formula (III-B1) is a compound of Formula (III- B1*) or Formula (III-B1**) [0108] Targeting compounds of Formula (III-B1) may be prepared by a process that includes reacting a compound of Formula (I-B1) with R 21 -R 1a , where Table B provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5,
  • R 21 may be conjugated to moiety R 42a by reaction of complementary chemical functional groups R 1 (e.g., represented by –X 1 -W 1 in Table B) and R 1a to form linker L 1 (e.g., represented by –X 1 - LL 1 in Table B).
  • R 1 complementary chemical functional groups
  • R 1a e.g., represented by –X 1 -W 1 in Table B
  • linker L 1 e.g., represented by –X 1 - LL 1 in Table B.
  • R 21 -R 1a may include a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A or an antigen-binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment of any one thereof; or an antibody codrituzumab (GC33), or a binding fragment of any one thereof).
  • a protein e.g., one of the representative antibodies disclosed in Table A or an antigen-binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment of any one thereof; or an antibody codrituzumab (GC33), or a binding fragment of any one thereof).
  • R 1 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table B, where R 1 (e.g., represented by –X 1 -W 1 in Table B) may be selected to selectively react with R 1a in order to provide L 1 (e.g., represented by –X 1 -LL 1 in Table B) of Formula (III-B1).
  • R 1 e.g., represented by –X 1 -W 1 in Table B
  • L 1 e.g., represented by –X 1 -LL 1 in Table B
  • the structures include compounds of Formula (I- B2) (e.g., compounds of Formula (I-B2*) or Formula (I-B2**)); a therapeutic radiopharmaceutical agent comprising a compound of Formula (I-B2) or pharmaceutically acceptable salt and/or solvate thereof and a radionuclide; a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (I-B2) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide; compounds of Formula (II-B2) (e.g., compounds of Formula (II-B2*) or Formula (II-B2**)); a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (II-B2) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide
  • a compound of Formula (I-B2) is a compound of Formula (I- B2*) or Formula (I-B2**)
  • a compound of Formula (II-B2) is a compound of Formula (II- B2*) or Formula (II-B2**)
  • a compound of Formula (III-B2) is a compound of Formula (III- B2*) or Formula (III-B2**)
  • Targeting compounds of Formula (III-B2) may be prepared by a process that includes reacting a compound of Formula (I-B2) with R 21 -R 1a , where Table B provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).
  • R 21 may be conjugated to moiety R 42b by reaction of complementary chemical functional groups R 10 (e.g., represented by –X 1 -W 1 in Table B) and R 1a to form linker L 1 (e.g., represented by –X 1 - LL 1 in Table B).
  • R 21 -R 1a may include a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A or an antigen-binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment of any one thereof; or an antibody codrituzumab (GC33), or a binding fragment of any one thereof).
  • a protein e.g., one of the representative antibodies disclosed in Table A or an antigen-binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment of any one thereof; or an antibody codrituzumab (GC33), or a binding fragment of any one thereof).
  • R 10 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table B, where R 10 (e.g., represented by –X 1 -W 1 in Table B) may be selected to selectively react with R 1a in order to provide L 1 (e.g., represented by –X 1 -LL 1 in Table B) of Formula (III-B2).
  • a therapeutic radiopharmaceutical agent described herein comprises a compound and a radionuclide, where the compound is or a pharmaceutically acceptable salt and/or solvate thereof.
  • a compound of Formula (II-B1) or (II-B2) is or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is a radionuclide.
  • M 1 is a radionuclide.
  • a modified antibody, modified antibody fragment, or modified binding peptide of the present technology it may be that the modified antibody, modified antibody fragment, or modified binding peptide comprises a moiety having the following structure wherein one of the hydrogens is being substituted by a linkage or a pharmaceutically acceptable salt and/or solvate thereof.
  • modified antibody, modified antibody fragment, or modified binding peptide of the present technology it may be that the modified antibody, modified antibody fragment, or modified binding peptide comprises a moiety having the following structure wherein one of the hydrogens is being substituted by a linkage or a pharmaceutically acceptable salt and/or solvate thereof.
  • the structures include compounds of Formula (I-C1); a therapeutic radiopharmaceutical agent comprising a compound of Formula (I-C1) or pharmaceutically acceptable salt and/or solvate thereof and a radionuclide; a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (I-C1) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide; compounds of Formula (II- C1); a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (II-C1) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide; and targeting compounds of Formula (III-C1).
  • a therapeutic radiopharmaceutical agent comprising a compound of Formula (I-C1) or pharmaceutically acceptable salt and/or solvate thereof and a radionuclide
  • Targeting compounds of Formula (III-C1) may be prepared by a process that includes reacting a compound of Formula (I-C1) or (II-C1) with R 21 -R 1a , where Table B provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).
  • R 21 may be conjugated to macrocycle R 43a by reaction of complementary chemical functional groups R 1 (e.g., represented by –X 1 -W 1 in Table B) and R 1a to form linker L 1 (e.g., represented by –X 1 -LL 1 in Table B).
  • R 1 complementary chemical functional groups
  • R 1a e.g., represented by –X 1 -W 1 in Table B
  • linker L 1 e.g., represented by –X 1 -LL 1 in Table B.
  • R 21 -R 1a may include a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A or an antigen-binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment of any one thereof; or an antibody codrituzumab (GC33), or a binding fragment of any one thereof).
  • a protein e.g., one of the representative antibodies disclosed in Table A or an antigen-binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment of any one thereof; or an antibody codrituzumab (GC33), or a binding fragment of any one thereof).
  • R 1 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table B, where R 1 (e.g., represented by –X 1 -W 1 in Table B) may be selected to selectively react with R 1a in order to provide L 1 (e.g., represented by –X 1 -LL 1 in Table B) of Formula (III- C1) [0120]
  • the structures include compounds of Formula (I-C2); a therapeutic radiopharmaceutical agent comprising a compound of Formula (I-C2) or pharmaceutically acceptable salt and/or solvate thereof and a radionuclide; a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (I-C2) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide; compounds of Formula (II- C2); a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage
  • Targeting compounds of Formula (III-C2) may be prepared by a process that includes reacting a compound of Formula (I-C2) or (II-C2) with R 25 -R 5a , where Table C provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). As such, R 25 may be conjugated to macrocycle R 43b by reaction of complementary chemical functional groups R 5 and R 5a to form linker L 5 .
  • R 25 -R 5a may include a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A or an antigen-binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment of any one thereof; or an antibody codrituzumab (GC33), or a binding fragment of any one thereof).
  • R 5 may include a reactive chemical functional moiety, non- limiting examples of which are disclosed in the Table C, where R 5 may be selected to selectively react with R 5a in order to provide L 5 of Formula (III-C2).
  • a therapeutic radiopharmaceutical agent described herein comprises a compound and a radionuclide, where the compound is or a pharmaceutically acceptable salt and/or solvate thereof.
  • a compound of Formula (II-C1) or (II-C2) is or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is a radionuclide.
  • modified antibody, modified antibody fragment, or modified binding peptide of the present technology it may be that the modified antibody, modified antibody fragment, or modified binding peptide comprises a moiety having the following structure wherein one of the hydrogens is being substituted by a linkage or a pharmaceutically acceptable salt and/or solvate thereof.
  • modified antibody, modified antibody fragment, or modified binding peptide comprises a moiety having the following structure wherein one of the hydrogens is being substituted by a linkage or a pharmaceutically acceptable salt and/or solvate thereof.
  • the structures include compounds of Formula (I-D1); a therapeutic radiopharmaceutical agent comprising a compound of Formula (I-D1) or pharmaceutically acceptable salt and/or solvate thereof and a radionuclide; a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (I-D1) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide; compounds of Formula (II- D1); a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (II-D1) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide; and targeting compounds of Formula (III-D1).
  • a therapeutic radiopharmaceutical agent comprising a compound of Formula (I-D1) or pharmaceutically acceptable salt and/or solvate thereof and a radionuclide
  • Targeting compounds of Formula (III-D1) may be prepared by a process that includes reacting a compound of Formula (I-D1) or (II-D1) with R 21 -R 1a , where Table B provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).
  • R 21 may be conjugated to macrocycle R 44a by reaction of complementary chemical functional groups R 1 (e.g., represented by –X 1 -W 1 in Table B) and R 1a to form linker L 1 (e.g., represented by –X 1 -LL 1 in Table B).
  • R 1 complementary chemical functional groups
  • R 1a e.g., represented by –X 1 -W 1 in Table B
  • linker L 1 e.g., represented by –X 1 -LL 1 in Table B.
  • R 21 -R 1a may include a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A or an antigen-binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment of any one thereof; or an antibody codrituzumab (GC33), or a binding fragment of any one thereof).
  • a protein e.g., one of the representative antibodies disclosed in Table A or an antigen-binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment of any one thereof; or an antibody codrituzumab (GC33), or a binding fragment of any one thereof).
  • R 1 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table B, where R 1 (e.g., represented by –X 1 -W 1 in Table B) may be selected to selectively react with R 1a in order to provide L 1 (e.g., represented by –X 1 -LL 1 in Table B) of Formula (III- D1).
  • R 1 e.g., represented by –X 1 -W 1 in Table B
  • L 1 e.g., represented by –X 1 -LL 1 in Table B
  • the structures include compounds of Formula (I-D2); a therapeutic radiopharmaceutical agent comprising a compound of Formula (I-D2) or pharmaceutically acceptable salt and/or solvate thereof and a radionuclide; a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (I-D2) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide; compounds of Formula (II- D2); a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (II-D2) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide; and targeting compounds of Formula (III-D2).
  • a therapeutic radiopharmaceutical agent comprising a compound of Formula (I-D2) or pharmaceutically acceptable salt and/or solvate thereof and a radionuclide
  • Targeting compounds of Formula (III-D2) may be prepared by a process that includes reacting a compound of Formula (I-D2) or (II-D2) with R 21 -R 1a , where Table B provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10).
  • R 21 may be conjugated to macrocycle R 44b by reaction of complementary chemical functional groups R 10 (e.g., represented by –X 1 -W 1 in Table B) and R 1a to form linker L 1 (e.g., represented by –X 1 -LL 1 in Table B).
  • R 10 complementary chemical functional groups
  • R 1a linker L 1 (e.g., represented by –X 1 -LL 1 in Table B).
  • R 21 -R 1a may include a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A or an antigen-binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment of any one thereof; or an antibody codrituzumab (GC33), or a binding fragment of any one thereof).
  • a protein e.g., one of the representative antibodies disclosed in Table A or an antigen-binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment of any one thereof; or an antibody codrituzumab (GC33), or a binding fragment of any one thereof).
  • R 10 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table B, where R 10 (e.g., represented by –X 1 -W 1 in Table B) may be selected to selectively react with R 1a in order to provide L 1 (e.g., represented by –X 1 -LL 1 in Table B) of Formula (III-D2).
  • R 10 e.g., represented by –X 1 -W 1 in Table B
  • L 1 e.g., represented by –X 1 -LL 1 in Table B
  • the structures include compounds of Formula (I-D3); a therapeutic radiopharmaceutical agent comprising a compound of Formula (I-D3) or pharmaceutically acceptable salt and/or solvate thereof and a radionuclide; a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (I-D3) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide; compounds of Formula (II- D3); a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (II-D3) or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide; and targeting compounds of Formula (III-D3).
  • a therapeutic radiopharmaceutical agent comprising a compound of Formula (I-D3) or pharmaceutically acceptable salt and/or solvate thereof and a radionuclide
  • Targeting compounds of Formula (III-D3) may be prepared by a process that includes reacting a compound of Formula (I-D3) or (II-D3) with R 25 -R 5a , where Table C provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10). As such, R 25 may be conjugated to macrocycle R 44c by reaction of complementary chemical functional groups R 5 and R 5a to form linker L 5 .
  • R 25 -R 5a may include a modified target amino acid residue within a protein (e.g., one of the representative antibodies disclosed in Table A or an antigen-binding fragment thereof; a PSMA binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound, or a binding fragment of any one thereof; or an antibody codrituzumab (GC33), or a binding fragment of any one thereof).
  • R 5 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table C, where R 5 may be selected to selectively react with R 5a in order to provide L 5 of Formula (III-D3).
  • a therapeutic radiopharmaceutical agent described herein comprises a compound and a radionuclide, where the compound is or a pharmaceutically acceptable salt and/or solvate thereof.
  • a compound of Formula (II-D1), (II-D2), or (II-D3) is or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is a radionuclide.
  • modified antibody, modified antibody fragment, or modified binding peptide of the present technology it may be that the modified antibody, modified antibody fragment, or modified binding peptide comprises a moiety having the following structure wherein one of the hydrogens is being substituted by a linkage or a pharmaceutically acceptable salt and/or solvate thereof.
  • modified antibody, modified antibody fragment, or modified binding peptide comprises a moiety having the following structure wherein one of the hydrogens is being substituted by a linkage or a pharmaceutically acceptable salt and/or solvate thereof.
  • Table B Exemplary Preparation for Targeting Compounds of Formula (III-A), Formula (III-B1), Formula (IP-B2), Formula (III-C1), Formula (III- Dl), and Formula (III-D2).
  • Amide coupling is typically mediated by any of several coupling reagents (e.g., HATU, EDC, DCC, HOBT, PyBOP, etc.), which are detailed elsewhere. (See generally Eric Valeur & Mark Bradley, Amide Bond Formation: Beyond the Myth of Coupling Reagents, 38 CHEM. SOC. REV.606 (2009).) These and other amide coupling strategies are described in a recent review by Tsuchikama. (Kyoji Tsuchikama & Zhiqiang An, Antibody-Drug Conjugates: Recent Advances in Conjugation and Linker Chemistries, 9 PROTEIN CELL 33, 36 (2018); see also, e.g., A.C.
  • cysteine coupling reactions may be employed to conjugate prosthetic molecules with thiol-reactive termini to protein surfaces through exposed thiol side chains on cysteine residues on the protein (e.g., antibody) surface.
  • cysteine residues readily form disulfide linkages with nearby cysteine residues under physiological conditions, rather than existing as free thiols, some cysteine coupling strategies may rely upon selective reduction of disulfides to generate a higher number of reactive free thiols.
  • Cysteine coupling techniques known in the art include, but are not limited to, cys alkylation reactions, cysteine rebridging reactions, and cys-aryl coupling using organometallic palladium reagents.
  • ADCs Antibody-Drug Conjugates
  • CuAAC copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction
  • the CuAAC click reaction may be carried out in the presence of ligands to enhance reaction rates.
  • ligands may include, for example, polydentate nitrogen donors, including amines (e.g., tris(triazolyl)methyl amines) and pyridines. (See Liang & Astruc, supra, at 2934 (collecting examples); P.L.
  • Cu-free click methods are also known in the art for delivery of therapeutic and/or diagnostic agents, such as radionuclides (e.g., 18 F), chemotherapeutic agents, dyes, contrast agents, fluorescent labels, chemiluminescent labels, or other labels, to protein surfaces. Cu-free click methods may permit stable covalent linkage between target molecules and prosthetic groups.
  • Cu-free click chemistry may include reacting an antibody or antigen- binding fragment, which has been modified with a non-natural amino acid side chain that includes an activating moiety such as a cyclooctyne (e.g., dibenzocyclooctyne (DBCO)), a nitrone or an azide group, with a prosthetic group that presents a corresponding or complementary reactive moiety, such as an azide, nitrone or cyclooctyne (e.g., DBCO).
  • an activating moiety such as a cyclooctyne (e.g., dibenzocyclooctyne (DBCO)
  • DBCO dibenzocyclooctyne
  • a prosthetic group that presents a corresponding or complementary reactive moiety, such as an azide, nitrone or cyclooctyne (e.g., DBCO).
  • the prosthetic group may include an azide, nitrone, or similar reactive moiety.
  • the prosthetic group may present a complementary cyclooctyne, alkyne, or similar reactive moiety.
  • Cu-free click reactions may be carried out at room temperature, in aqueous solution, in the presence of phosphate-buffered saline (PBS).
  • the prosthetic group may be radiolabeled (e.g., with 18 F) or may be conjugated to any alternative diagnostic and/or therapeutic agent (e.g., a chelating agent). (See id. at 531.)
  • Tripartite Compounds [0140] The compounds of any embodiment and aspect herein of the present technology may be a tripartite compound. However, such tripartite compounds are not restricted to compositions including Formulas (I), (II), or (III).
  • a tripartite compound that includes a first domain that has relatively low but still specific affinity for serum albumin (e.g., 0.5 to 50 x 10 -6 M), a second domain including a chelating moiety such as but not limited to those described herein (e.g., a chelating moiety comprising or arising from a compound of Formula (I) or Formula (II)), and a third domain that includes tumor targeting moiety (TTT) having relatively high affinity for a tumor antigen (e.g., 0.5 to 50 x 10 -9 M).
  • TTT tumor targeting moiety
  • the following exemplary peptide receptors, enzymes, cell adhesion molecules, tumor associated antigens, growth factor receptors and cluster of differentiation antigens are useful targets for constructing the TTT domain: glypican-3 (GPC3) receptor, somatostatin peptide receptor-2 (SSTR2), gastrin- releasing peptide receptor, seprase (FAP-alpha), incretin receptors, glucose-dependent insulinotropic polypeptide receptors , VIP-1, NPY, folate receptor, LHRH, and ⁇ v ⁇ 3, an overexpressed peptide receptor, a neuronal transporter (e.g., noradrenaline transporter (NET)), or other tumor associated proteins such as EGFR, HER-2, VGFR, MUC-1, CEA, MUC-4, ED2,TF-antigen, endothelial specific markers, neuropeptide Y, uPAR, TAG-72, CCK analogs, VIP, bombesin, VEGFR, tumor-specific cell surface proteins, G
  • TTT is independently at each occurrence a binding domain for a glypican-3 (GPC3) receptor, a somatostatin peptide receptor-2 (SSTR2), a gastrin-releasing peptide receptor, a seprase (FAP-alpha), an incretin receptor, a glucose-dependent insulinotropic polypeptide receptor, VIP-1, NPY, a folate receptor, LHRH, ⁇ v ⁇ 3, an overexpressed peptide receptor, a neuronal transporter (e.g., noradrenaline transporter (NET)), a receptor for a tumor associated protein (such as EGFR, HER-2, VGFR, MUC-1, CEA, MUC-4, ED2,TF-antigen, endothelial specific markers, neuropeptide Y, uPAR, TAG-72, CCK analogs, VIP, bombesin, VEGFR, tumor-specific cell surface proteins, GLP-1, CXCR4, Hepsin, TMPRSS2, caspaces,
  • L 501 is independently at each occurrence absent, -C(O)-, -C(O)-NR 4 -, -C(O)-NR 5 -C 1 -C 12 alkylene-,-C 1 -C 12 alkylene-C(O)-, -C(O)-NR 6 -C 1 -C 12 alkylene-C(O)-, -arylene-, – O(CH 2 CH 2 O)r–CH 2 CH 2 C(O)–, –O(CH 2 CH 2 O) rr –CH 2 CH 2 C(O)–NH—, – O(CH 2 CH 2 O) rrr –CH 2 CH 2 —, an amino acid, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids, or a combination of any two or more thereof, where r is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, rr is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, rrr is 0, 1, 2, 3, 4, 5, 6, 7, 8, or
  • the radionuclide may be 230 UO 2 2+ , 230 U 6+ , 67 Ga 3+ , 68 Ga 3+ , 64 Cu 2+ , or 111 In 3+ .
  • it may be the tripartite compounds of Formulas (L)-(LIV) are of Formulas (LV)-(LIX) where L 503 is independently at each occurrence absent, -C(O)-, -C 1 -C 12 alkylene-,-C 1 -C 12 alkylene-C(O)-, -C 1 -C 12 alkylene-NR 10 -, -arylene-, –(CH 2 CH 2 O) z –CH 2 CH 2 C(O)–, – (CH 2 CH 2 O) zz –CH 2 CH 2 C(O)–NH–, –(CH 2 CH 2 O) zzz –CH 2 CH 2 –, an amino acid, —CH
  • the albumin-binding moiety plays a role in modulating the rate of blood plasma clearance of the compounds in a subject, thereby increasing circulation time and compartmentalizing the cytotoxic action of cytotoxin-containing domain and/or imaging capability of the imaging agent-containing domain in the plasma space instead of normal organs and tissues that may express antigen.
  • this component of the structure is believed to interact reversibly with serum proteins, such as albumin and/or cellular elements.
  • the affinity of this albumin-binding moiety for plasma or cellular components of the blood may be configured to affect the residence time of the compounds in the blood pool of a subject.
  • the albumin binding-moiety may be configured so that it binds reversibly or non-reversibly with albumin when in blood plasma. In any embodiment herein, the albumin binding-moiety may be selected such that the binding affinity of the compound with human serum albumin is about 5 ⁇ M to about 15 ⁇ M.
  • the albumin-binding moiety of any embodiment herein may include a short- chain fatty acid, medium-chain chain fatty acid, a long-chain fatty acid, myristic acid, a substituted or unsubstituted indole-2-carboxylic acid, a substituted or unsubstituted 4- oxo-4-(5,6,7,8-tetrahydronaphthalen-2-yl)butanoic acid, a substituted or unsubstituted naphthalene acylsulfonamide, a substituted or unsubstituted diphenylcyclohexanol phosphate ester, a substituted or unsubstituted 2-(4-iodophenyl)acetic acid, a substituted or unsubstituted 3- (4-iodophenyl)propionic acid, or a substituted or unsubstituted 4-(4-iodophenyl)but
  • the tripartite compounds may include an albumin-binding moiety that is where Y 501 502 , Y , Y 503 , Y 504 , and Y 505 are independently H, halo, or alkyl, X 503 , X 504 , X 505 , and X 506 are each independently O or S, aa is independently at each occurrence 0, 1, or 2, bb is independently at each occurrence 0 or 1, cc is independently at each occurrence 0 or 1, and dd is independently at each occurrence 0, 1, 2, 3, or 4. In any embodiment herein, it may be that bb and cc cannot be the same value.
  • Y 503 is I and each of Y 501 , Y 502 , Y 503 , Y 504 , and Y 505 are each independently H.
  • Representative chelators useful in any embodiment of the present technology include, but are not limited to, a covalently conjugated substituted or unsubstituted chelator of the following group: 6,6'-((ethane-1,2-diylbis(azanediyl))bis(methylene))dipicolinic acid (H 2 dedpa), 6,6'-((((1S,2S)-cyclohexane-1,2-diyl)bis(azanediyl))bis(methylene))dipicolinic acid (H 2 CHXdedpa), 2,2'-((ethane-1,2-diylbis(azanediyl))bis(methylene))bis(quinolin-8-ol) (H 2 ho
  • a “covalently conjugated” chelator means a chelator (such as those listed above) wherein one or more bonds to a hydrogen atom contained therein are replaced by a bond to an atom of the remainder of the Rad and/or CHEL moiety, to L 501 , and/or to L 502 , or a pi bond between two atoms is replaced by a bond from one of the two atoms to an atom of the remainder of the Rad and/or CHEL moiety, to L 501 , and/or to L 502 , and the other of the two atoms includes a new bond, e.g. to a hydrogen.
  • the CHEL of the tripartite compounds is a chelator as provided in the compounds of Formula (I), (II), or (III).
  • tripartite compound may be a targeting compound of Formula (III) where R 21 , R 25 , R 26 , R 27 , and R 28 are each independently
  • TTT may be an antibody.
  • TTT may be codrituzumab (GC33), or a binding fragment thereof.
  • TTT may be a targeting moiety that targets the glypican-3 (GPC3) receptor.
  • TTT comprises a targeting moiety that targets the glypican-3 (GPC3) receptor.
  • TTT may be any embodiment
  • W 501 is –C(O)–, –(CH 2 ) ww –, or –(CH 2 ) oo –NH 2 -C(O)–; mm is 0 or 1; ww is 1 or 2; oo is 1 or 2;and P 501 , P 502 , and P 503 are each independently H, methyl, benzyl, 4-methoxybenzyl, or tert- butyl. [0152] In any embodiment herein, it may be that each of P 501 , P 502 , and P 503 are H.
  • the tripartite compounds e.g., the tumor targeting domain
  • the tripartite compounds comprise a moiety with one of the following structures, which may, e.g., target seprase (Fibroblast Activation Protein/FAP):
  • target seprase Fibroblast Activation Protein/FAP
  • the tripartite compounds of the present technology can include variations on any of the three domains: e.g., the domain including the chelator, the domain including the albumin-binding group, or the domain including the tumor targeting moiety.
  • compositions e.g., pharmaceutical compositions
  • medicaments comprising any of one of the embodiments of the compounds of Formulas (I), (II), (III); any one of therapeutic radiopharmaceutical agents comprising a chelator (e.g., compounds of Formulas (I)) and a radionuclide (e.g., 230 U); any one of the modified antibodies, modified antibody fragments, or modified binding peptides of the present technology disclosed herein; or any one of the embodiments of the tripartite compounds disclosed herein, and a pharmaceutically acceptable carrier or one or more excipients or fillers (collectively referred to as “pharmaceutically acceptable carrier” unless otherwise specified).
  • a pharmaceutically acceptable carrier or one or more excipients or fillers
  • compositions may be used in the methods and treatments described herein.
  • the pharmaceutical composition may include an effective amount of any embodiment of the compounds of the present technology for treating the cancer and/or mammalian tissue overexpressing e.g., an antigen or a receptor; or an effective amount of any embodiment of the modified antibody, modified antibody fragment, or modified binding peptide of the present technology for treating the cancer and/or mammalian tissue overexpressing e.g., an antigen or a receptor; or an effective amount of any embodiment of the tripartite compound of the present technology for treating the cancer and/or mammalian tissue overexpressing e.g., an antigen or a receptor.
  • a method of treating a subject includes administering a targeting compound of the present technology to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of the present technology to the subject.
  • a targeting compound of the present technology to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of the present technology to the subject.
  • the administering includes administering an effective amount of any embodiment of the compounds of the present technology for treating the cancer and/or mammalian tissue overexpressing, e.g., an antigen or a receptor of the compound or an effective amount of any embodiment of the modified antibody, modified antibody fragment, or modified binding peptide of the present technology for treating the cancer and/or mammalian tissue overexpressing, e.g., an antigen or a receptor or an effective amount of any embodiment of the tripartite compound of the present technology for treating the cancer and/or mammalian tissue overexpressing e.g., an antigen or a receptor.
  • the subject may suffer from a mammalian tissue expressing glypican-3 (GPC3) receptor, a somatostatin receptor, a bombesin receptor, seprase, or a combination of any two or more thereof and/or mammalian tissue overexpressing PSMA.
  • the mammalian tissue of any embodiment disclosed herein may include one or more of a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, a neuroblastoma, and a metastatic cancer.
  • the subject may suffer from one or more of a liver cancer, a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.
  • the composition e.g., pharmaceutical composition
  • medicament may be formulated for parenteral administration.
  • the composition e.g., pharmaceutical composition
  • the administering step of the method may include parenteral administration.
  • the administering step of the method may include intraveneous administration.
  • the effective amount may be determined in relation to a subject. “Effective amount” refers to the amount of a compound or composition required to produce a desired effect.
  • an effective amount includes amounts or dosages that yield acceptable toxicity and bioavailability levels for therapeutic (pharmaceutical) use including, but not limited to, the treatment of e.g., one or more of a glioma, a liver cancer, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non- small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.
  • an effective amount includes amounts or dosages that are capable of reducing symptoms associated with e.g., one or more of a glioma, a liver cancer, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non- small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer, such as, for example, reduction in proliferation and/or metastasis of liver cancer, prostate cancer, breast cancer, or bladder cancer.
  • a glioma a liver cancer, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non- small cell
  • the effective amount may be from about 0.01 ⁇ g to about 1 mg of the compound per gram of the composition, and preferably from about 0.1 ⁇ g to about 500 ⁇ g of the compound per gram of the composition.
  • a “subject” or “patient” is a mammal, such as a cat, dog, rodent or primate.
  • the subject is a human, and, preferably, a human suffering from or suspected of suffering from one or more of a glioma, a liver cancer, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer (such as colon adenocarcinoma), a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.
  • the term “subject” and “patient” can be used interchangeably.
  • the pharmaceutical composition may be packaged in unit dosage form.
  • the unit dosage form is effective in treating one or more of a cancer, a liver cancer, a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer (such as colon adenocarcinoma), a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.
  • a unit dosage including a 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 therapies and the like. An exemplary unit dosage based on these considerations may also be adjusted or modified by a physician skilled in the art.
  • a unit dosage for a patient comprising a compound of the present technology may vary from 1 ⁇ 10 –4 g/kg to 1 g/kg, preferably, 1 ⁇ 10 –3 g/kg to 1.0 g/kg. Dosage of a compound of the present technology may also vary from 0.01 mg/kg to 100 mg/kg or, preferably, from 0.1 mg/kg to 10 mg/kg.
  • Suitable unit dosage forms include, but are not limited to powders, tablets, pills, capsules, lozenges. suppositories. patches. nasal sprays, injectibles, implantable sustained-release formulations, rnucoadherent films, topical varnishes, lipid complexes, etc.
  • the pharmaceutical compositions may be prepared by mixing one or more of the compounds of Formulas (I), (II), (III); or a therapeutic radiopharmaceutical agent comprising a chelator (e.g., compounds of Formulas (I)) and a radionuclide (e.g., 230 U); or any one of the modified antibodies, modified antibody fragments, or modified binding peptides of the present technology, or any embodiment of the tripartite compound of the present technology, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof, with pharmaceutically acceptable carriers, excipients, binders, diluents or the like to prevent and treat disorders associated with cancer (e.g., liver cancer) and/or a mammalian tissue overexpressing glypican-3 (GPC3) receptor.
  • a therapeutic radiopharmaceutical agent comprising a chelator (e.g., compounds of Formulas (I)) and a radionuclide (e.g.,
  • compositions described herein may be used to prepare formulations and medicaments that treat e.g., liver cancer, prostate cancer, breast cancer, or bladder cancer.
  • Such compositions may be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions.
  • the instant compositions may be formulated for various routes of administration, for example, by oral, parenteral, topical, rectal, nasal, vaginal administration, or via implanted reservoir.
  • 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.
  • powders, suspensions, granules, tablets, pills, capsules, gelcaps, and caplets are acceptable as solid dosage forms. These can be prepared, for example, by mixing one or more compounds of the instant present technology, or pharmaceutically acceptable salts or tautomers thereof, with at least one additive such as a starch or other additive.
  • Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, collagens, casein, albumin, synthetic or semi-synthetic polymers or glycerides.
  • oral dosage forms can contain other ingredients to aid in administration, such as an inactive diluent, or lubricants such as magnesium stearate, or preservatives such as paraben or sorbic acid, or anti-oxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Tablets and pills may be further treated with suitable coating materials known in the art.
  • suitable coating materials known in the art.
  • Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, and solutions, which may contain an inactive diluent, such as water.
  • Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using a sterile liquid, such as, but not limited to, an oil, water, an alcohol, and combinations of these.
  • Pharmaceutically suitable surfactants, suspending agents, emulsifying agents may be added for oral or parenteral administration.
  • suspensions may include oils.
  • oils include, but are not limited to, peanut oil, sesame oil, cottonseed oil, com oil and olive oil.
  • Suspension preparation may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides.
  • Suspension formulations may include alcohols, such as, but not limited to, ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol.
  • Injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent. Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be employed as solvents or suspending agents.
  • the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
  • the pharmaceutical formulation and/or medicament may be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • Compounds of the present technology may 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 appropriate solvents and optionally other compounds such as, but not limited to, stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols.
  • Aqueous and nonaqueous aerosols are typically used for delivery of compounds of the present technology by inhalation.
  • pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant present technology. Such excipients and carriers are described, for example, in “Remingtons Pharmaceutical Sciences” Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.
  • the instant compositions may also include, for example, micelles or liposomes, or some other encapsulated form.
  • Specific dosages may be adjusted depending on conditions of disease, the age, body weight, general health conditions, sex, and diet of the subject, dose intervals, administration routes, excretion rate, and combinations of drugs. Any of the above dosage forms containing effective amounts are well within the bounds of routine experimentation and therefore, well within the scope of the instant present technology. [0167] Various assays and model systems can be readily employed to determine the therapeutic effectiveness of the treatment according to the present technology.
  • test subjects will exhibit a 10%, 20%, 30%, 50% or greater reduction, up to a 75–90%, or 95% or greater, reduction, in one or more symptom(s) caused by, or associated with, the disorder in the subject, compared to placebo–treated or other suitable control subjects.
  • the present technology provides a method of treating cancer by administering an effective amount of the targeting composition according to Formula (III) to a subject having cancer. Since a cancer cell targeting agent can be selected to target any of a wide variety of cancers, the cancer considered herein for treatment is not limited.
  • the cancer can be essentially any type of cancer.
  • antibodies or peptide vectors can be produced to target any of a wide variety of cancers.
  • the targeting compositions described herein are typically administered by injection into the bloodstream, but other modes of administration, such as oral or topical administration, are also considered.
  • the targeting composition may be administered locally, at the site where the target cells are present, i.e., in a specific tissue, organ, or fluid (e.g., blood, cerebrospinal fluid, etc.). Any cancer that can be targeted through the bloodstream is of particular consideration herein.
  • a specific tissue, organ, or fluid e.g., blood, cerebrospinal fluid, etc.
  • Any cancer that can be targeted through the bloodstream is of particular consideration herein.
  • Some examples of applicable body parts containing cancer cells include the breasts, lungs, stomach, intestines, prostate, ovaries, cervix, pancreas, kidney, liver, skin, lymphs, bones, bladder, uterus, colon, rectum, and brain.
  • the cancer can also include the presence of one or more carcinomas, sarcomas, lymphomas, blastomas, or teratomas (germ cell tumors).
  • the cancer may also be a form of leukemia.
  • the cancer is a triple negative breast cancer.
  • the cancer is a liver cancer.
  • a suitable dosage of the targeting composition may be precisely, at least, above, up to, or less than, for example, 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 a dosage within a range bounded by any of the foregoing exemplary dosages.
  • compositions can be administered in the indicated amount by any suitable schedule, e.g., once, twice, or three times a day or on alternate days for a total treatment time of one, two, three, four, or five days, or one, two, three, or four weeks, or one, two, three, four, five, or six months, or within a time frame therebetween.
  • schedule e.g., once, twice, or three times a day or on alternate days for a total treatment time of one, two, three, four, or five days, or one, two, three, or four weeks, or one, two, three, four, five, or six months, or within a time frame therebetween.
  • the composition can be administered until a desired change in the disorder or condition is realized, or when a preventative effect is believed to be provided.
  • the examples herein are provided to illustrate advantages of the present technology and to further assist a person of ordinary skill in the art with preparing or using the compounds of the present technology or salts, pharmaceutical compositions, derivatives, prodrugs, or
  • Deionized water ( ⁇ 18 M ⁇ ) was obtained from an Elga Purelab Flex 2 water purification system.
  • Analytical high performance liquid chromatography HPLC was performed using a LC- 20AT pump with an SPD-20AV UV-vis detector monitored at 270 and 220 nm (Shimadzu, Japan) and an Ultra Aqueous C18 column (100 ⁇ , 5 ⁇ m, 250 mm ⁇ 4.6 mm; Restek, Bellefonte, PA) at a flow rate of 1 mL/min. All methods employed a binary mobile phase.
  • Method A1 (A) H 2 O + 0.1% TFA; (B) MeOH + 0.1% TFA; 0-5 min 10% B, 5-25 min linear gradient to 100% B, 25-30 min 100% B, 30-35 min linear gradient to 10% B.
  • Method A2 (A) H 2 O + 50 mM NH 4 OAc; (B) MeOH + 50 mM NH 4 OAc, 0-5 min 10% B, 5-25 min linear gradient to 100% B, 25-30 min 100% B, 30-35 min linear gradient to 10% B.
  • Method A3 (A) H 2 O + 50 mM NH 4 OAc; (B) MeOH + 50 mM NH 4 OAc, 0-5 min 10% B, 5-15 min linear gradient to 100% B, 15-20 min 100% B, 20- 25 min linear gradient to 10% B.
  • Method A4 (A) H 2 O + 10 mM NH 4 HCO 3 ; (B) 90% MeOH + 10% H 2 O + 10 mM NH 4 HCO 3 , 0-5 min 10% B, 5-15 min linear gradient to 100% B, 15-20 min 100% B, 20-25 min linear gradient to 10% B.
  • Method P1 (A) H 2 O + 0.1% TFA; (B) MeOH + 0.1% TFA; 0-5 min 10% B, 5-25 min linear gradient to 100% B, 25-30 min 100% B, 30-35 min linear gradient to 10% B.
  • NMR spectra were obtained at 25 °C using a Varian Inova 600 MHz spectrometer equipped with a H ⁇ C/N ⁇ probe with XYZ-PFG, a Bruker AV III HD 400 MHz spectrometer equipped with a broadband BBFO probe, or a Bruker AV III HD 500 MHz spectrometer equipped with a broadband Prodigy cryoprobe.
  • Samples containing 238 U were obtained using a Varian Inova 500 MHz spectrometer equipped with a 1 H/BB nanoprobe with Z-PFG. Chemical shifts are reported in ppm and were referenced to the residual solvent signal.
  • Spectra acquired in D 2 O were spiked with 0.1% dioxane, 0.1% acetone, or 0.1% DMSO-d 6 as an internal reference.
  • Spectra of samples containing 238 U were collected in an NMR tube fitted with a PTFE liner (C-TL-5-7; Chemglass Life Sciences, Vineland, NJ) to prevent release of 238 U in the case of a tube break.
  • MS High resolution mass spectra
  • MS were recorded on an Exactive Orbitrap mass spectrometer (ThermoFisher) in positive ion electrospray ionization (ESI) mode with samples injected as acetonitrile/water solutions with 1% formic acid or direct analysis in real time (DART) mode with samples dissolved in chloroform.
  • UV-vis spectra were recorded using 1 cm quartz cuvettes and a Shimadzu UV-1900 spectrometer (Shimadzu, Kyoto, Japan) fitted with a temperature-controlled circulating water bath. Infrared spectra were recorded in KBr pellets using a Nicolet Avatar 370 DTGS (ThermoFisher Scientific, Waltham, MA).
  • Elemental analyses were carried out by Atlantic Microlab Inc. (Norcross, GA).
  • Uranium stock solutions were prepared either by dissolving a weighed amount of UO 2 (NO 3 ) 2 ⁇ 6H 2 O in 0.1M HCl for the complexation kinetics studies or from an inductively coupled plasma standardized solution (9992 ⁇ 44 ⁇ g/mL, 2 % v/v HNO 3 ; BDH Chemicals) for all other studies and the exact concentration was determined using arsenazo III with a calibration curve prepared using a series of UO 2 (NO 3 ) 2 solutions with known concentration.
  • Synthesis and Characterization of H 2 dedpa H 2 dedpa was prepared according to below procedure.
  • Ethylene diamine (380 ⁇ L, 5.7 mmol) was dissolved in MeOH (38 mL) and added dropwise to a solution of S2 (1.9 g, 11.5 mmol) in boiling MeOH (115 mL) with rapid stirring. The resulting solution was heated at reflux for 30 min and allowed to cool to RT. The yellow solution was filtered, and the solvent was removed by rotary evaporation to give a yellow residue, which was suspended in Et 2 O (40 mL) and filtered to furnish a white powder. Yield: 1.44 g, 4.06 mmol (71%).
  • H 2 CHXdedpa H 2 CHXdedpa was prepared according to below procedure. [0190] ( ⁇ )- ⁇ [(6-(methoxycarbonyl)pyridin-2-yl)-methylene]amino ⁇ -cyclohexane (S5).
  • H 2 hox was prepared according to below procedure.
  • 2-formyl-8-hydroxyquinoline (S7) A mixture of dioxane (300 mL) and water (3 mL) was bubbled with Ar for 30 min and transferred via cannula to a flask containing 2-methyl-8-hyroxyquinoline (4.067 g, 25.5 mmol) and SeO 2 (3.55 g, 32.03 mmol) under an Ar atmosphere. The resulting suspension was heated at 80 °C for 24 h under an Ar atmosphere to yield an orange solution, which was cooled to RT and filtered to remove elemental Se.
  • H 2 CHXhox was prepared according to below procedure.
  • S9 2,2'-[( ⁇ )-1,2-cyclohexanediylbis(nitrliomethylidyne)]bis(8-quinolinol) (S9).
  • S9 2,2'-[( ⁇ )-1,2-cyclohexanediylbis(nitrliomethylidyne)]bis(8-quinolinol) (S9).
  • S7 1.017 g, 5.87 mmol
  • Triethylamine (61 ⁇ L, 0.441 mmol) was added to a methanolic solution (6 mL) of H 2 CHXdedpa ⁇ 2HCl (0.0717 g, 0.152 mmol) and stirred at room temperature.
  • a solution of UO 2 (NO 3 ) 2 ⁇ 6H 2 O (0.0482 g, 0.096 mmol) in MeOH (1 mL) was added dropwise to the reaction mixture to give a bright yellow solution with almost immediate formation of a pale yellow precipitate.
  • the suspension was heated at reflux for 13 h, allowed to cool to RT, and added to an equal volume of Et 2 O to fully precipitate the product.
  • Triethylamine (27 ⁇ L, 0.193 mmol) was added to a methanolic solution (3 mL) of H 2 hox ⁇ 2HCl (0.0294 g, 0.0657 mmol) and stirred at room temperature.
  • a solution of UO 2 (NO 3 ) 2 ⁇ 6H 2 O (0.0212 g, 0.0421 mmol) in MeOH (0.5 mL) was added dropwise to the reaction mixture, which rapidly changed color from yellow to orange to brown with formation of a brown precipitate.
  • the suspension was heated at reflux for 18 h and cooled to RT before an equal volume of Et 2 O was added to fully precipitate the product, which was collected by centrifugation.
  • Triethylamine (56 ⁇ L, 0.4 mmol) was added to a methanolic solution (6 mL) of H 2 CHXhox ⁇ 2HCl (0.0502 g, 0.089 mmol) and stirred at room temperature.
  • the suspension was heated at reflux for 16 h and cooled to RT before an equal volume of Et 2 O was added to fully precipitate the product, which was collected by centrifugation.
  • the ligand protonation constants were measured by adding KOH to an aqueous solution ( ⁇ 20 mL) containing ligand ( ⁇ 1 mM) and HCl (5 mM). The ionic strength of the solution was maintained at 0.1 M using KCl.
  • the titration method employed a 0.1 mV min -1 drift limit with a minimum and maximum wait time of 10 s and 200 s respectively between addition of aliquots of base.
  • the titration data was analyzed using Hyperquad2013. Results are summarized in Table 1. [0217] In Situ Spectrophotometric Titration.
  • Stock solutions of the ligands were prepared in pure water at a typical concentration of approximately 1.5 mM for H 2 hox or 10 mM for H 2 CHXhox, and the exact concentration was determined by quantitative NMR spectroscopy in triplicate.
  • Titration solutions were prepared containing the ligand ( ⁇ 25 ⁇ M) and 500 ⁇ M (20 equiv.) each of MOPS, MES, and CHES to dampen the pH change upon addition of base.
  • the ionic strength of each titration solution was maintained at 0.1 M using KCl. The solution was allowed to equilibrate with stirring for 15 min before addition of 0.01 – 1 mL aliquots of KOH.
  • the pH of each sample was adjusted with standardized 1 M or 0.1 M HCl to span the range 0.7 ⁇ pH ⁇ 2.4 (H 2 dedpa and H 2 CHXdedpa) or 2.4 ⁇ pH ⁇ 7 (H 2 hox and H 2 CHXhox).
  • pH ⁇ 1 the ionic strength was adjusted to 0.1 M with KCl.
  • pH ⁇ 1 the ionic strength was dictated by the HCl concentration. All samples were allowed to equilibrate at 25 °C for at least 24 h. The pH-dependent spectroscopic data were analyzed using HypSpec 2014.
  • a ⁇ is the final absorbance value
  • At is the absorbance at time t.
  • Absorbance was measured at 265 nm for H 2 dedpa, 268 nm for H 2 CHXdedpa, 260 nm for H 2 hox, and 260 nm for H 2 CHXhox.
  • the second order rate constant k 2 (M -1 s -1 ) for the complexation reaction was then calculated as the linear slope of kobs vs. [H 2 L]. Results are summarized in Table 2. Table 2.
  • Second-Order Rate Constants (k 2 , M –1 s –1 ) and Half-Lives (t 1/2 , s) for the Complexation of UO 2 2+ by the Ligands at 25 °C in Aqueous Solution.
  • the second-order half-lives for the complexation reactions calculated using concentrations of 10 ⁇ M for both L and UO 2 2+ , are all under 4 min.
  • the complexation kinetics for H 2 hox and H 2 CHXhox showed a marked dependence on pH with significantly smaller second-order rate constants obtained at pH 5 compared to pH 7.4, which may be a consequence of the fact that the ligands are fully protonated at lower pH.
  • H 2 CHXdedpa the binding kinetics of the less basic H 2 dedpa and H 2 CHXdedpa ligands are relatively invariant to these two pH conditions.
  • Comparison of the complexation kinetics of H 2 CHXdedpa and H 2 depda highlights the favorable effect of the preorganized CHX backbone towards metal chelation; H 2 CHXdedpa can sequester free uranium twice as fast as its en-based counterpart.
  • the CHX group appears to have little influence on the complexation kinetics of H 2 hox and H 2 CHXhox.
  • HAP hydroxyapatite
  • caffeine 20 ⁇ M; H 2 CHXdedpa and H 2 CHXhox) or thiourea (1 mM; H 2 dedpa and H 2 hox) as an internal standard for HPLC analysis.
  • the final complex concentration was 50 ⁇ M for UO 2 (dedpa) and UO 2 (CHXdedpa), 20 ⁇ M for H 2 hox, and 5 ⁇ M H 2 CHXhox.
  • Uranyl nitrate in 1% nitric acid was purchased from International Bio- Analytical Industries (Boca Raton, FL) and used for complexation as described, and buffered to a final pH of 7 in sodium bicarbonate and Tris prior to injection.
  • ligand evaluation groups a 1:0.7 ratio of ligand to metal was used.
  • animals were sacrificed by CO 2 asphyxiation and organs of interest harvested.
  • the organs were digested in ultra pure nitric acid (FisherSci) in trace metal-free vessels with a graded heating protocol from 65 ⁇ C by 10 ⁇ C for 15 min increments and then maintained at 95 ⁇ C for 1 h (DigiTUBE and DigiPREP Jr.; SCP Science, Montreal, Canada).
  • the digested tissues were filtered through 0.45 ⁇ m polyethersulfone polymer membranes (Autofill; Foxx Life Science, Salem, NH) after dilution with deionized water to 14% nitric acid content, and then further diluted for analysis to 1-3%.
  • a compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof wherein Z 1 is R 5 , and Z 2 is R 6 ; or Z 1 and Z 2 taken together are a C4 alkylene group optionally substituted by R 9 ; Z 3 is R 7 , and Z 4 is C(O); or Z 3 and Z 4 taken together with the carbon atoms to which they are bound are a 6-membered aryl ring optionally substituted by R 10 ; Z 5 is R 8 , and Z 6 is C(O); or Z 5 and Z 6 are taken together with the carbon atoms to which they are bound are a 6-membered aryl ring optionally substituted by R 11 ; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently H, OH, NH 2 , SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl
  • a therapeutic radiopharmaceutical agent comprising a chelator and a radionuclide; wherein the chelator is a compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, wherein Z 1 is R 5 , and Z 2 is R 6 ; or Z 1 and Z 2 taken together are a C 4 alkylene group optionally substituted by R 9 ; Z 3 is R 7 , and Z 4 is C(O); or Z 3 and Z 4 taken together with the carbon atoms to which they are bound are a 6-membered aryl ring optionally substituted by R 10 ; Z 5 is R 8 , and Z 6 is C(O); or Z 5 and Z 6 are taken together with the carbon atoms to which they are bound are a 6-membered aryl ring optionally substituted by R 11 ; R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently H, OH, NH 2 , SH,
  • the therapeutic radiopharmaceutical agent of Paragraph J wherein Z 1 and Z 2 taken together are a C 4 alkylene group optionally substituted by R 9 .
  • the therapeutic radiopharmaceutical agent of Paragraph J or K wherein the compound of Formula (I) is a compound of Formula (I-A) or a pharmaceutically acceptable salt and/or solvate thereof.
  • N The therapeutic radiopharmaceutical agent of Paragraph M, wherein the compound of Formula (I-A) is a compound of Formula (I-A*) or Formula (I-A**) or a pharmaceutically acceptable salt and/or solvate thereof.
  • O. The therapeutic radiopharmaceutical agent of any one of Paragraphs J, K, and M, wherein the chelator compound is , or a pharmaceutically acceptable salt and/or solvate thereof.
  • the therapeutic radiopharmaceutical agent of Paragraph O wherein the chelator compound is , or a pharmaceutically acceptable salt and/or solvate thereof.
  • Q The therapeutic radiopharmaceutical agent of any one of Paragraphs J-L, wherein the compound of Formula (I) is a compound of Formula (I-Bl) or Formula (I-B2), or a pharmaceutically acceptable salt and/or solvate thereof.
  • R The therapeutic radiopharmaceutical agent of any one of Paragraphs J-L and Q, wherein the compound of Formula (I-Bl) or Formula (I-B2) is a compound of Formula (I-Bl*), Formula (I-Bl**), Formula (I-B2*), or Formula (I-B2**), or a pharmaceutically acceptable salt and/or solvate thereof.
  • a compound of Formula (II) or a pharmaceutically acceptable salt and/or solvate thereof wherein M 1 is 230 U 67 Ga, 68 Ga, 64 Cu, or 111 In, optionally where M 1 is 230 UO 2 2+ , 230 U 6+ , 67 Ga 3+ , 6 8 Ga 3+ , 64 Cu 2+ , or 111 In 3+ ; Z 1 is R 5 , and Z 2 is R 6 ; or Z 1 and Z 2 taken together are a C 4 alkylene group optionally substituted by R 9 ; Z 3 is R 7 , and Z 4 is C(O); or Z 3 and Z 4 taken together with the carbon atoms to which they are bound are a 6-membered aryl ring optionally substituted by R 10 ; Z 5 is R 8 , and Z 6 is C(O); or Z 5 and Z 6 are taken together with the carbon atoms to which they are bound are a 6-membered aryl ring optionally substituted by R 11 ; R 1 , R 2
  • R 21 , R 25 , R 26 , R 27 , and R 28 each independently comprises codrituzumab (GC33), belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, At
  • the targeting compound of Paragraph NN or OO wherein the compound is a compound of Formula (III-A) or a pharmaceutically acceptable salt and/or solvate thereof.
  • QQ The targeting compound of Paragraph PP, wherein the compound is a compound of
  • the targeting compound of Paragraph NN or OO wherein the compound is a compound of Formula (III-B1) or Formula (III-B2) pharmaceutically acceptable salt and/or solvate thereof.
  • the targeting compound of Paragraph RR wherein the compound is a compound of Formula (III-B1*), Formula (III-B1**), or Formula (III-B2*), or Formula (III-B2**)
  • the targeting compound of Paragraph NN or OO wherein the compound is a compound of Formula (III-C1) or Formula (III-C2) or a pharmaceutically acceptable salt and/or solvate thereof.
  • VV The therapeutic radiopharmaceutical agent of any one of Paragraphs NN-UU, wherein M 1 is 230 UO 2 .
  • WW A modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (I) or a pharmaceutically acceptable salt and/or solvate thereof, or a pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide, wherein Z 1 is R 5 , and Z 2 is R 6 ; or Z 1 and Z 2 taken together are a C 4 alkylene group optionally substituted by R 9 ; Z 3 is R 7 , and Z 4 is C(O); or Z 3 and Z 4 taken together with the carbon atoms to which they are bound are a 6-membered aryl ring optionally substituted by R 10 ; Z 5 is R 8 , and Z 6 is C(O); or Z 5 and Z 6 are taken together with the carbon
  • the modified antibody, modified antibody fragment, or modified binding peptide of Paragraph WW wherein the antibody comprises codrituzumab (GC33), belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelum
  • the modified antibody, modified antibody fragment, or modified binding peptide of Paragraph WW wherein the antibody fragment comprises an antigen-binding fragment of codrituzumab (GC33), belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab,
  • CCC The modified antibody, modified antibody fragment, or modified binding peptide of Paragraph AAA, wherein the compound of Formula (I-B1) or Formula (I-B2) is a compound of Formula (I-B1*), Formula (I-B1**), Formula (I-B2*), or Formula (I- B2**), or a pharmaceutically acceptable salt and/or solvate thereof.
  • DDD The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs WW-YY, wherein the compound of Formula (I) is a compound of Formula (I-B1) or Formula (I-B2), or a pharmaceutically acceptable salt and/or solvate thereof.
  • the modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs WW-YY wherein the compound of Formula (I) is a compound of Formula (I-C1) or Formula (I-C2), or a pharmaceutically acceptable salt and/or solvate thereof.
  • EEE The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs WW-YY, wherein the compound of Formula (I) is a compound of Formula (I-D1), Formula (I-D2), or Formula (I-D3) or a pharmaceutically acceptable salt and/or solvate thereof.
  • FFF is a compound of Formula (I-D1), Formula (I-D2), or Formula (I-D3) or a pharmaceutically acceptable salt and/or solvate thereof.
  • a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula (II) or a pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide, wherein M 1 is 230 U, 67 Ga, 68 Ga, 64 Cu, or 111 In, optionally where M 1 is 230 UO 2 2+ , 230 U 6+ , 67 Ga 3+ , 6 8 Ga 3+ , 64 Cu 2+ , or 111 In 3+ ; Z 1 is R 5 , and Z 2 is R 6 ; or Z 1 and Z 2 taken together are a C 4 alkylene group optionally substituted by R 9 ; Z 3 is R 7 , and Z 4 is C(O); or Z 3 and Z 4 taken together with the carbon atoms to which they are bound are a 6-membered aryl ring optionally substituted by R 10 ; Z 5 is R 8 , and Z 6 is C(O); or Z 5 and Z
  • the modified antibody, modified antibody fragment, or modified binding peptide of Paragraph EEE wherein the antibody comprises codrituzumab (GC33), belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine, Siltuximab, Cemiplimab, Nivolumab, Pembrolizumab, Olaratumab, Atezolizumab, Avelum
  • Paragraph JJJ wherein the compound of Formula (II-B) is a compound of Formula (II- Bl*), Formula (II-Bl**), Formula (II-B2*), or Formula (II-B2**). or a pharmaceutically acceptable salt and/or solvate thereof.
  • MMM The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs EEE-HHH, wherein the compound of Formula (II) is a compound of Formula (II-C1) or Formula (II-C2), or a pharmaceutically acceptable salt and/or solvate thereof.
  • NNN The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs EEE-HHH, wherein the compound of Formula (II) is a compound of Formula (II-C1) or Formula (II-C2), or a pharmaceutically acceptable salt and/or solvate thereof.
  • the modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs EEE-HHH wherein the compound of Formula (II) is a compound of Formula (II-D1), Formula (II-D2) or Formula (II-D3), or a pharmaceutically acceptable salt and/or solvate thereof.
  • OOO The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs EEE-NNN, wherein M 1 is 230 UO 2 .
  • PPP A composition comprising a pharmaceutically acceptable carrier and a compound of any one of Paragraphs A-I and Z-MM, or a therapeutic radiopharmaceutical agent of any one of Paragraphs J-Y. QQQ.
  • a composition comprising a pharmaceutically acceptable carrier and a targeting compound of any one of Paragraphs NN-VV or comprising a pharmaceutically acceptable carrier and a modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs WW-NNN.
  • RRR A pharmaceutical composition useful in targeted radiotherapy of cancer and/or mammalian tissue in a subject, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of any one of Paragraphs NN-VV or a modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs WW-NNN.
  • the pharmaceutical composition of Paragraph RRR wherein the pharmaceutical composition comprises an effective amount for treating the cancer and/or mammalian tissue of the compound, or an effective amount for treating the cancer and/or mammalian tissue of the modified antibody, modified antibody fragment, or modified binding peptide.
  • TTT The pharmaceutical composition of any one of Paragraphs PPP-SSS, wherein the subject suffers from one or more of, a growth hormone producing tumor, a neuroendocrine tumor, a pituitary tumor, a vasoactive intestinal peptide-secreting tumor, a small cell carcinoma of the lung, gastric cancer tissue, pancreatic cancer tissue, and a neuroblastoma.
  • any one of Paragraphs PPP-TTT wherein the subject suffers from one or more of a liver cancer, a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma, a primary colorectal adenocarcinoma, a renal cell carcinoma, and a prostate cancer.
  • a liver cancer a glioma, a breast cancer, an adrenal cortical cancer, a cervical carcinoma, a vulvar carcinoma, an endometrial carcinoma, a primary ovarian carcinoma, a metastatic ovarian carcinoma, a non-small cell lung cancer, a small cell lung cancer, a bladder cancer, a colon cancer, a primary gastric adenocarcinoma,
  • the pharmaceutical composition of any one of Paragraphs PPP-UUU wherein the pharmaceutical composition is formulated for intraveneous administration, optionally comprising sterilized water, Ringer's solution, or an isotonic aqueous saline solution.
  • WWW The pharmaceutical composition of any one of PPP-VVV, wherein the effective amount of the compound is from about 0.01 ⁇ g to about 10 mg of the compound per gram of the pharmaceutical composition.
  • XXX The pharmaceutical composition of any one of Paragraphs PPP-WWW, wherein the pharmaceutical composition is provided in an injectable dosage form.
  • a method of treating a subject comprising administering a targeting compound of any one of Paragraphs NN-VV to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs WW-NNN.
  • AAAA The method of Paragraph YYY or ZZZ, wherein the administering comprises parenteral administration.
  • CCCC The method of any one of Paragraphs YYY-BBBB, wherein the effective amount is from about 0.1 ⁇ g to about 50 ⁇ g per kilogram of subject mass.
  • a compound comprising a first domain having a blood-protein binding moiety with low specific affinity for the blood-protein, a second domain having a targeting antibody or a fragment thereof, and a third domain having a chelator.
  • the compound of Paragraph DDDD wherein the blood protein binding moiety has specific affinity for albumin of about 0.5-50 x 10 -6 M, and the targeting antibody or a fragment thereof has specific affinity of about 0.5-50 x 10 -9 M.

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  • Life Sciences & Earth Sciences (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente technologie concerne des composés, ainsi que des compositions comprenant de tels composés, utiles en radiothérapie ciblée (par exemple, une thérapie à l'uranium) de cancer et/ou de tissu de mammifère surexprimant, par exemple, un antigène ou un récepteur, les composés étant représentés par les formules suivantes ou par un de leurs sels et/ou solvates pharmaceutiquement acceptables, M1 étant indépendamment, à chaque occurrence, un radionucléide. L'invention divulgue également des équivalents de tels composés.
PCT/US2022/031157 2021-05-26 2022-05-26 Complexes à chélateurs acycliques et leur utilisation en radiothérapie ciblée de cancer WO2022251516A2 (fr)

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CA2783275A1 (fr) * 2003-07-24 2005-02-03 Bracco Imaging S.P.A. Compositions radiopharmaceutiques stables et methodes pour leur preparation
EP2895204B1 (fr) * 2012-09-13 2020-10-21 Provincial Health Services Authority Compositions ciblant le récepteur b1 de la bradykinine pour l'imagerie médicale du cancer et d'autres troubles
GB201417067D0 (en) * 2014-09-26 2014-11-12 South African Nuclear Energy Radiopharmaceutical conjugate
KR20210110834A (ko) * 2018-12-18 2021-09-09 프로빈셜 헬스 서비시즈 오쏘리티 이중 방식의 18f-표지된 테라노스틱 화합물 및 그 용도

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