WO2022251541A1 - Macrocycles et complexes avec des radionucléides utiles dans la radiothérapie ciblée du cancer - Google Patents

Macrocycles et complexes avec des radionucléides utiles dans la radiothérapie ciblée du cancer Download PDF

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WO2022251541A1
WO2022251541A1 PCT/US2022/031196 US2022031196W WO2022251541A1 WO 2022251541 A1 WO2022251541 A1 WO 2022251541A1 US 2022031196 W US2022031196 W US 2022031196W WO 2022251541 A1 WO2022251541 A1 WO 2022251541A1
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independently
occurrence
formula
compound
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WO2022251541A9 (fr
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Nikki THIELE
Justin J. Wilson
Aohan HU
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Cornell University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems
    • 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
    • A61K51/0402—Organic compounds carboxylic acid carriers, fatty acids
    • 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
    • A61K51/0482—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 chelates from cyclic ligands, e.g. DOTA
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • a compound of any one of Formula I, Formula II, Formula III, and Formlua IV is provided or a pharmaceutically acceptable salt and/or solvate thereof, wherein A 1 , A 2 , A 3 , and A 4 are each independently R 2 is independently at each occurrence R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); 3 4 the other one of Y and Y is O; one of Y 5 and Y 6 is , , or , and the other one of Y 5 and Y 6 is O, or Y 5 and Y 6 are each independently , , , or ; one Z 2 , Z 3 , Z 4 , Z 5
  • M 1 is a radionuclide chelated in the compound
  • a 1 , A 2 , A 3 , and A 4 are each independently
  • R 2 is independently at each occurrence
  • R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -);
  • Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , and Z 13 are independently at each occurrence H or –X 1 –W 2 ;
  • Z 1 is independently at each occurrence OH or NH–W 3 ;
  • Z 9 is independently at each occurrence H, -S(O) 2 OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X 1 –W 2 ;
  • ⁇ is independently at each occurrence 0 or 1;
  • X 1 is independently at each occurrence O, NH, or S;
  • X 2 is independently at each occurrence OH, SH, NH 2 , N(CH 3 )H, or N(CH 3 ) 2 ;
  • X 3 is independently at each occurrence OH, SH, NH2, N(CH 3 )H, or N
  • the present technology provides a targeting compound useful in, e.g., useful in targeted radiotherapy of cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”), where the targeting compound is of any one of Formula V, Formula VI, Formula VII, and Formula VIII or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is a radionuclide chelated in the targeting compound;
  • a 5 , A 6 , A 7 , and A 8 are each independently R 2 is independently at each occurrence
  • R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); 3 4 the other one of Y and Y is O;
  • Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , and Z 13 are independently at each occurrence H or –X 1 –L 3 –R 22 ;
  • Z 1 is independently at each occurrence OH or NH–L 4 –R 24 ;
  • Z 9 is independently at each occurrence H, -S(O) 2 OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –L 5 –R 26 ;
  • ⁇ is independently at each occurrence 0 or 1;
  • X 1 is independently at each occurrence O, NH, or S;
  • X 2 is independently at each occurrence OH, SH, NH 2 , N(CH 3 )H, or N(CH 3 ) 2 ;
  • X 3 is independently at each occurrence OH, SH, NH2, N(
  • a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of any one of Formula I, Formula II, Formula III, and Formlua IV 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 any one of Formula IA, Formula IIA, Formula IIIA, and Formlua IVA or a pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide.
  • compositions e.g., pharmaceutical compositions
  • medicaments comprising any of one of the embodiments of the compounds disclosed herein, any one of the embodiments of the targeting compounds disclosed herein, or any one of the modified antibodies, modified antibody fragments, or modified binding peptides of the present technology disclosed herein, and a pharmaceutically acceptable carrier or one or more excipients or fillers (collectively refered to as “pharmaceutically acceptable carrier” unless otherwise specified).
  • pharmaceutically acceptable carrier one or more excipients or fillers
  • FIG.1 shows stability constants of Ln 3+ complexes formed with py-macrodipa and macrodipa plotted versus ionic radii.
  • FIG.3 shows crystal structures of (a) [La(py-macrodipa)] + , (b) [Lu(py-macrodipa)] + , and (c) [Sc(py-macrodipa)(OH2)] + complexes.
  • Thermal ellipsoids are drawn at the 50% probability level. Solvent, counterions, and nonacidic hydrogen atoms are omitted for clarity. Only one of the two [La(py-macrodipa)] + or [Sc(py-macrodipa)(OH 2 )] + complexes in the asymmetric unit is shown.
  • FIGs.4A-4C show DFT-computed standard free energies regarding the conformational toggle of Ln 3+ ⁇ py-macrodipa (FIGs.4A-4B) and Ln 3+ ⁇ macrodipa (FIG.4C) complexes.
  • FIG.5 shows calculated strain energies ( ⁇ GS°) values for Ln 3+ ⁇ py-macrodipa and Ln 3+ ⁇ macrodipa systems.
  • FIG.6 shows 1 H NMR spectrum of compound A5 (500 MHz, CDCl3, 25 °C).
  • FIG.7 shows 13 C NMR spectrum of compound of A5 (126 MHz, CDCl3, 25 °C).
  • FIG.8 shows 1 H NMR spectrum of compound A6 (500 MHz, CDCl 3 , 25 °C).
  • FIG.9 shows 13 C NMR spectrum of compound A6 (126 MHz, CDCl 3 , 25 °C).
  • FIG.10 shows 1 H NMR spectrum of compound A8 (500 MHz, MeOD, 25 °C).
  • FIG.13 shows 1 H NMR spectrum of compound A8 (500 MHz, D 2 O, 25 °C).
  • FIG.14 shows 13 C NMR spectrum of compound A8 (126 MHz, D2O, 25 °C).
  • FIG.15 shows ESI-HRMS of compound A9.
  • FIG.16 shows 1 H NMR spectrum of dimethyl ester of compound A10 (500 MHz, MeOD, 25 °C).
  • FIG.17 shows ESI-HRMS of dimethyl ester of compound A10.
  • FIG.18 shows 1 H NMR spectrum of compound A10 (500 MHz, D 2 O, 25 °C).
  • FIG.19 shows ESI-HRMS of compound A10.
  • FIG.20 shows 1 H NMR spectrum of py-macrodipa-NCS (A11) (500 MHz, DMSO, 25 °C).
  • FIG.21 shows ESI-HRMS of py-macrodipa-NCS (A11).
  • FIG. 22 shows HPLC chromatogram of purified py-macrodipa-NCS.
  • FIG.23 shows aqueous stability of py-macrodipa-NCS over time examined by HPLC.
  • FIG. 24 shows HPLC chromatogram of purified Hf(IV)-py-macrodipa.
  • FIG.25 shows stability constants of Ln 3+ complexes formed with EDTA, OBETA, and macropa plotted versus ionic radii.
  • FIG.26 shows stability constants of Ln 3+ complexes formed with macrodipa and macrotripa plotted versus ionic radii.
  • FIG.28 shows crystal structures of (a) [La(macrodipa)] + , (b) [Lu(macrodipa)(OH 2 )] + , and (c) [La(macrotripa)] + complexes. Thermal ellipsoids are drawn at the 50% probability level. Solvent, counterions, and nonacidic hydrogen atoms are omitted for clarity. Only one of the two [La(macrodipa)] + complexes in the asymmetric unit is shown. [0037] FIG.29 shows DFT-computed standard free energies for the conformational equilibrium (eq 4) of Ln 3+ -macrodipa complexes.
  • FIG.30 shows depiction of the conformational toggle present in Ln 3+ -Macrodipa and Ln 3+ -macrotripa complex systems.
  • FIG.31 shows 1 H NMR (500 MHz, CDCl 3 , 25 °C) and 13 C ⁇ 1 H ⁇ NMR (126 MHz, CDCl3, 25 °C) spectra of 3.
  • FIG. 32 shows 1H NMR (500 MHz, D 2 O, pD ⁇ 8 by NaOD, 25 °C) and 13C ⁇ 1H ⁇ NMR (126 MHz, D 2 O, pD ⁇ 8 by NaOD, 25 °C) spectra of macrodipa. Acetonitrile was added as an internal reference.
  • Acetonitrile was added as an internal reference
  • FIG.34 shows ESI-HRMS of 3. MeCN was used as the mobile phase.
  • FIG.35 shows ESI-HRMS of 5. MeCN was used as the mobile phase.
  • FIG.36 shows ESI-HRMS of macrodipa. MeCN was used as the mobile phase.
  • FIG.37 shows ESI-HRMS of 9.
  • FIG.38 shows ESI-HRMS of macrotripa. MeCN was used as the mobile phase.
  • FIG.39 shows HPLC chromatogram of macrodipa. Method: 0–5 min, 90% H 2 O/MeOH; 5–25 min, 90% ⁇ 0% H 2 O/MeOH.
  • FIG. 40 shows HPLC chromatogram of macrotripa. Method: 0–5 min, 90% H 2 O/MeOH; 5–25 min, 90% ⁇ 0% H 2 O/MeOH.
  • FIG.50 shows representative stability constant determination of Tb-macrodipa system by potentiometric titration.
  • cTb 9 ⁇ 10 -4 M
  • cmacrodipa 1 ⁇ 10 -3 M.
  • Initial volume V 15 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 0.893.
  • FIG.56 shows representative stability constant determination of Lu-macrodipa system by potentiometric titration.
  • Initial volume V 15 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 0.759.
  • FIG.56 shows representative stability constant determination of Lu-macrodipa system by potentiometric titration.
  • FIG.57 shows representative stability constant determination of La-macrotripa system by potentiometric titrations.
  • cLa 1 ⁇ 10 -3 M
  • cmacrotripa 1 ⁇ 10 -3 M.
  • Initial volume V 20 mL.
  • FIG.58 shows representative stability constant determination of Ce-macrotripa system by potentiometric titration.
  • cCe 1 ⁇ 10 -3 M
  • cmacrotripa 1 ⁇ 10 -3 M.
  • Initial volume V 20 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 2.731.
  • FIG.59 shows representative stability constant determination of Pr-macrotripa system by potentiometric titration.
  • cPr 1 ⁇ 10 -3 M
  • cmacrotripa 1 ⁇ 10 -3 M
  • Initial volume V 20 mL.
  • FIG.60 shows representative stability constant determination of Nd-macrotripa system by potentiometric titration.
  • cNd 1 ⁇ 10 -3 M
  • cmacrotripa 1 ⁇ 10 -3 M.
  • Initial volume V 20 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 1.493.
  • FIG.61 shows representative stability constant determination of Sm-macrotripa system by potentiometric titration.
  • cSm 1 ⁇ 10 -3 M
  • cmacrotripa 1 ⁇ 10 -3 M
  • Initial volume V 20 mL.
  • FIG.62 shows representative stability constant determination of Eu-macrotripa system by potentiometric titration.
  • cEu 1 ⁇ 10 -3 M
  • cmacrotripa 1 ⁇ 10 -3 M.
  • Initial volume V 20 mL. Data fitting and speciation distribution over the titration pH range are shown.
  • FIG.63 shows representative stability constant determination of Gd-macrotripa system by potentiometric titration.
  • cGd 1 ⁇ 10 -3 M
  • cmacrotripa 1 ⁇ 10 -3 M
  • Initial volume V 20 mL.
  • Data fitting and speciation distribution over the titration pH range are shown.
  • Sigma value of this refinement 0.787.
  • FIG.64 shows representative stability constant determination of Tb-macrotripa system by potentiometric titration.
  • cTb 1 ⁇ 10 -3 M
  • cmacrotripa 1 ⁇ 10 -3 M.
  • Initial volume V 20 mL.
  • FIG.67 shows representative stability constant determination of Er-macrotripa system by potentiometric titration.
  • cEr 1 ⁇ 10 -3 M
  • cmacrotripa 1 ⁇ 10 -3 M.
  • Initial volume V 20 mL.
  • FIG.68 shows representative stability constant determination of Tm-macrotripa system by potentiometric titration.
  • cTm 1 ⁇ 10 -3 M
  • cmacrotripa 1 ⁇ 10 -3 M.
  • Initial volume V 20 mL.
  • FIG.113 shows stacked 1 H NMR spectra La 3+ , Lu 3+ , and Y 3+ -macrodipa complexes.
  • FIG.114 shows stacked 13 C ⁇ 1 H ⁇ NMR spectra La 3+ , Lu 3+ , and Y 3+ -macrodipa complexes. Due to the limited sensitivity on 13 C nucleus, only the major Conformation B is observed in the 13 C ⁇ 1 H ⁇ spectrum of Y 3+ -macrodipa complex.
  • FIG.117 shows stacked 1 H NMR spectra La 3+ , Lu 3+ , and Y 3+ -macrotripa complexes. The 1 H spectrum of Y 3+ -macrotripa clearly shows the presence of only the Conformation B.
  • FIG.118 shows stacked 13 C ⁇ 1 H ⁇ NMR spectra La 3+ , Lu 3+ , and Y 3+ -macrotripa complexes.
  • FIG.120 shows 1 H NMR spectrum (500 MHz, D 2 O, pD ⁇ 6, 25 °C) of [La(macrodipa)][ClO4] crystals.
  • FIG.121 shows 1 H NMR spectrum (500 MHz, CD3OD, 25 °C) of [Lu(macrodipa)(OH2)][PF6] crystals.
  • FIG.122 shows 1 H NMR spectrum (500 MHz, DMSO-d6, 25 °C) of [La(Hmacrotripa)][BPh4] crystals.
  • FIG.124 shows ESI-HRMS of La-macrodipa complex. MeCN was used as the mobile phase.
  • FIG.125 shows ESI-HRMS of Lu-macrodipa complex. MeCN was used as the mobile phase.
  • FIG.126 shows ESI-HRMS of La-macrotripa complex. MeCN was used as the mobile phase.
  • FIG.127 shows ESI-HRMS of Lu-macrotripa complex. MeCN was used as the mobile phase.
  • FIG.128 shows DFT-optimized structure of [Lu(macrotripa)(OH2)] complex.
  • FIG.130 shows 1 H NMR spectrum (500 MHz, CD 3 OD, 25 °C) of the synthetic intermediate that is hydrolyzed to yield py-macrodiphoshpho.
  • FIG.131 shows 1 H NMR spectrum (500 MHz, D2O, 25 °C) of py-macrodiphoshpho. DETAILED DESCRIPTION [00140] The following terms are used throughout as defined below. [00141] As used herein and in the appended claims, singular articles such as “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
  • 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., SF5), sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amid
  • 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. [00165]
  • 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)-(C1-5 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 refers to –OH.
  • 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 –OCF3.
  • zido refers to –N 3 .
  • trialkyl ammonium refers to a –N(alkyl) 3 group. A trialkylammonium group is positively charged and thus typically has an associated anion, such as halogen anion.
  • trifluoromethyldiazirido refers t .
  • 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: .
  • all chemical formulas of the compounds described herein represent all tautomeric forms of compounds and are within the scope of the present technology.
  • Stereoisomers of compounds also known as optical isomers
  • Stereoisomers of compounds include all chiral, diastereomeric, and racemic forms of a structure, unless the specific stereochemistry is expressly indicated.
  • 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.
  • the macrocycles currently in use e.g., DOTA
  • the macrocycles currently in use generally form complexes of insufficient stability with radionuclides, particularly for radionuclides of larger size, such as actinium, radium, bismuth, and lead isotopes.
  • Such instability results in dissociation of the radionuclide from the macrocycle, and this results in a lack of selectivity to targeted tissue, which also results in toxicity to non-targeted tissue.
  • the present technology provides new macrocyclic complexes that are substantially more stable than those of the conventional art.
  • these new complexes can advantageously target cancer cells more effectively, with substantially less toxicity to non-targeted tissue than complexes of the art.
  • the new complexes can advantageously be produced at room temperature, in contrast to DOTA-type complexes, which generally require elevated temperatures (e.g., at least 80 °C) for complexation with the radionuclide.
  • the present technology also may employ alpha-emitting radionuclides instead of beta radionuclides. Alpha- emitting radionuclides are of much higher energy, and thus substantially more potent, than beta- emitting radionuclides.
  • a compound of any one of Formula I, Formula II, Formula III, and Formlua IV is provided or a pharmaceutically acceptable salt and/or solvate thereof, wherein A 1 , A 2 , A 3 , and A 4 are each independently R 2 is independently at each occurrence R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); the other one of Y 5 an 6 5 6 d Y is O, or Y and Y are each
  • Y 7 and Y 8 is O, or 7 8 Y and Y are each Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , and Z 13 are independently at each occurrence H or –X 1 –W 2 ;
  • Z 1 is independently at each occurrence OH or NH–W 3 ;
  • Z 9 is independently at each occurrence H, -S(O) 2 OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X 1 –W 2 ;
  • ⁇ is independently at each occurrence 0 or 1;
  • X 1 is independently at each occurrence O, NH, or S;
  • X 2 is independently at each occurrence OH, SH, NH2, N(CH 3 )H, or N(CH 3 ) 2 ;
  • X 3 is independently at each occurrence
  • M 1 is a radionuclide chelated in the compound
  • a 1 , A 2 , A 3 , and A 4 are each independently R 2 is independently at each occurrence
  • R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); one the other 3 4 one of Y and Y is O; one the other one of Y 5 and Y 6 is O 5 6 , or Y and Y are each the other 7 8 7 8 one of Y and Y is O, or Y and Y are each
  • Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , and Z 13 are independently at each occurrence H or –X 1 –W 2 ;
  • Z 1 is independently at each occurrence OH or NH–W 3 ;
  • Z 9 is independently at each occurrence H, -S(O) 2 OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X 1 –W 2 ;
  • ⁇ is independently at each occurrence 0 or 1;
  • X 1 is independently at each occurrence O, NH, or S;
  • X 2 is independently at each occurrence OH, SH, NH2, N(CH 3 )H, or N(CH 3 ) 2 ;
  • X 3 is independently at each occurrence OH, SH, NH 2 , N(CH 3 )H, or N
  • M 1 is independently at each occurrence actinium-225 ( 225 Ac 3+ ), lanthanum-132 ( 132 La 3+ ), lanthanum-135 ( 135 La 3+ ), lutetium-177 ( 177 Lu 3+ ), indium-111 ( 111 In 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and/or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium- 226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), uranium-230, scandium-44 ( 44 Sc 3+ ), scandium-47 ( 47 Sc 3+ ), gallium-67 ( 67 Ga 3+ ), or gall
  • the present technology provides a targeting compound useful in, e.g., useful in targeted radiotherapy of cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”), where the targeting compound is of any one of Formula V, Formula VI, Formula VII, and Formula VIII or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is a radionuclide chelated in the targeting compound;
  • a 5 , A 6 , A 7 , and A 8 are each independently R 2 is independently at each occurrence
  • R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); 3 4 the other one of Y and Y is O;
  • Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , and Z 13 are independently at each occurrence H or –X 1 –L 3 –R 22 ;
  • Z 1 is independently at each occurrence OH or NH–L 4 –R 24 ;
  • Z 9 is independently at each occurrence H, -S(O) 2 OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –L 5 –R 26 ;
  • ⁇ is independently at each occurrence 0 or 1;
  • X 1 is independently at each occurrence O, NH, or S;
  • X 2 is independently at each occurrence OH, SH, NH 2 , N(CH 3 )H, or N(CH 3 ) 2 ;
  • X 3 is independently at each occurrence OH, SH, NH2, N(
  • M 1 of the targeting compound may independently at each occurrence actinium-225 ( 225 Ac 3+ ), lanthanum-132 ( 132 La 3+ ), lanthanum-135 ( 135 La 3+ ), lutetium- 177 ( 177 Lu 3+ ), indium-111 ( 111 In 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+ and/or 212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), uranium-230, scandium-44 ( 44 Sc 3+ ), scandium-47 ( 47 Sc 3+ ), gallium-67 ( 67 Ga 3+ ), or gall
  • the binding peptide comprises comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement 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.
  • Scheme A [00206] Many neuroendocrine tumors express SSTR2 and the other somatostatin receptors.
  • somatostatin agonists e.g., Octreotide, Lanreotide
  • SSTR2 receptors Long acting somatostatin agonists
  • Zatelli MC et al., (Apr 2007).
  • 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 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), such as Fibroblast Activation Protein-alpha (FAP-alpha)
  • FAP Fibroblast Activation Protein-alpha
  • Seprase binding compounds include seprase inhibitors.
  • a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of any embodiment dislclosed herein of any one of Formula I, Formula II, Formula III, Formula IA, Formula IIA, and Formula IIIA (or 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 (e.g., a FAP-alpha binding compound), or a binding fragement thereof.
  • PSMA prostate specific membrane antigen
  • Targeting compounds may be prepared by a process that includes reacting with R 22 - W 1 a compound of any embodiment disclosed herein of Formula I, Formula II, Formula III, Formula IV, Formula IA, Formula IIA, Formula IIIA, or Formula IVA that includes –X 1 -W 2 group, where Table B provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and R 21 refers to the portion of the compound other than the –X 1 -W 2 group (this R 21 portion referred to as “macrocycle R 21 ”).
  • R 22 may be conjugated to macrocycle R 21 by reaction of complementary chemical functional groups W 1 and W 2 to form linker L 3 .
  • R 22 -W 1 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 (e.g., a FAP-alpha binding compound), or a binding fragement of any one thereof).
  • W 1 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table B, where W 2 may be selected to selectively react with W 1 in order to provide L 3 of the targeting compound.
  • Targeting compounds may be prepared by a process that includes reacting with R 24 - W 1 a compound of any embodiment disclosed herein of Formula I, Formula II, Formula III, Formula IV, Formula IA, Formula IIA, Formula IIIA, or Formula IVA that includes a –W 3 group, where Table C provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and R 23 refers to the portion of the compound other than the –W 3 group (this R 23 portion is referred to as “macrocycle R 23 ”).
  • R 24 may be conjugated to macrocycle R 23 by reaction of complementary chemical functional groups W 3 and W 4 to form linker L 4 .
  • R 24 -W 4 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 (e.g., a FAP-alpha binding compound), or a binding fragement of any one thereof).
  • W 4 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table C, where W 3 may be selected to selectively react with W 4 in order to provide L 4 of the target compound.
  • Table C. Targeting compounds may be prepared by a process that includes reacting with R 26 - W 6 a compound of any embodiment disclosed herein of Formula I, Formula II, Formula III, Formula IV, Formula IA, Formula IIA, Formula IIIA, or Formula IVA that includes a –W 5 group, where Table D provides representative examples (where n is independently at each occurrence 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) and R 25 refers to the portion of the compound other than the –W 5 group (this R 25 portion is referred to as “macrocycle R 25 ”).
  • R 26 may be conjugated to macrocycle R 25 by reaction of complementary chemical functional groups W 5 and W 6 to form linker L 5 .
  • R 26 -W 6 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 (e.g., a FAP-alpha binding compound), or a binding fragement of any one thereof).
  • W 6 may include a reactive chemical functional moiety, non-limiting examples of which are disclosed in the Table D, where W 5 may be selected to selectively react with W 6 in order to provide L 5 of the target compound.
  • amide coupling is a well-known route, where – as an example – lysine residues on the antibody surface react with terminal activated carboxylic acid esters to generate stable amide bonds.
  • Amide coupling is typically mediated by any of several coupling reagents (e.g., HATU, EDC, DCC, HOBT, PyBOP, etc.), which are detailed elsewhere.
  • 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
  • Protein conjugation strategies using non-natural amino acid side chains are also well-known in the art.
  • click chemistries provide access to conjugated proteins, by rapid and selective chemical transformations under a diverse range of reaction conditions. Click chemistries are known to yield peptide conjugates with limited by-product formation, despite the presence of unprotected functional groups, in aqueous conditions.
  • One important non-limiting example of a click reaction in the formation of conjugated peptides is the copper(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction (CuAAC).
  • Such ligands may include, for example, polydentate nitrogen donors, including amines (e.g., tris(triazolyl)methyl amines) and pyridines.
  • polydentate nitrogen donors including amines (e.g., tris(triazolyl)methyl amines) and pyridines.
  • amines e.g., tris(triazolyl)methyl amines
  • pyridines e.g., amines (e.g., tris(triazolyl)methyl amines)
  • Other widely-utilized click reactions include, but are not limited to, thiol-ene, oxime, Diels-Alder, Michael addition, and pyridyl sulfide reactions.
  • Copper-free (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).
  • PBS phosphate-buffered saline
  • 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.)
  • a chelating agent e.g., a chelating agent
  • 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 Formula I, Formula II, Formula III, Formula IV, Formula IA, Formula IIA, Formula IIIA, or Formula IVA.
  • a tripartite compound in an aspect, 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, 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).
  • TTTT tumor targeting moiety
  • somatostatin peptide receptor-2 SSTR2
  • gastrin- releasing peptide receptor SSTR2
  • FAP-alpha gastrin- releasing peptide receptor
  • incretin receptors glucose-dependent insulinotropic polypeptide receptors
  • VIP-1 NPY
  • folate receptor LHRH
  • ⁇ v ⁇ 3 an overexpressed peptide receptor
  • NET noradrenaline transporter
  • TTT is independently at each occurrence a binding domain for 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, 74
  • SSTR2 somatostatin peptide receptor-2
  • X 501 is independently at each occurrence absent, O, S, or NH;.
  • L 501 is independently at each occurrence absent, -C(O)-, -C(O)-NR 4 -, -C(O)-NR 5 -C1- C12 alkylene-,-C1-C12 alkylene-C(O)-, -C(O)-NR 6 -C1-C12 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,
  • the radionuclide may be 177 Lu 3+ , 175 Lu 3+ , 45 Sc 3+ , 66 Ga 3+ , 67 Ga 3+ , 68 Ga 3+ , 69 Ga 3+ , 71 Ga 3+ , 89 Y 3+ , 86 Y 3+ , 89 Zr 4+ , 90 Y 3+ , 99m Tc +1 , 111 In 3+ , 113 In 3+ , 115 In 3+ , 139 La 3+ , 136 Ce 3+ , 138 Ce 3+ , 140 Ce 3+ , 142 Ce 3+ , 151 Eu 3+ , 153 Eu 3+ , 152 Dy 3+ , 149 Tb 3+ , 159 Tb 3+ , 154 Gd 3+ , 155 Gd 3+ , 156 Gd 3+ , 157 Gd 3+ , 158 Gd 3+ , 160 Gd 3+ , 188 Re +1 ,
  • tripartite compounds of Formulas L-LIV are of Formulas LV-LIX 76
  • L 503 is independently at each occurrence absent, -C(O)-, -C1-C12 alkylene-,-C1-C12 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(CO2H)– (CH 2 )4–, –CH(CO2H)–(CH 2 )4–NH–, a peptide of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ,16, 17, 18, 19, or 20 amino acids, or a combination of any two or more thereof, where z is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ,16, 17, 18, 19, or 20 amino acids, or a combination
  • CHEL is independently at each occurrence a covalently conjugated chelator (of any embodiment disclosed herein of compounds of the present technology) that optionally includes a chelated radionuclide.
  • 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. Without being bound by theory, 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.
  • 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)
  • the tripartite compounds may include an albumin- binding moiety that is 79
  • Y 502 , 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
  • dd is independently at each occurrence 0, 1, 2, 3, or 4.
  • Y 503 is I and each of Y 501 , Y 502 , Y 503 , Y 504 , and Y 505 are each independently H.
  • the CHEL of the tripartite compounds is a chelator as provided in the compounds of Formula I, II, III, IA, IIA, or IIIA.
  • tripartite compound may be a targeting compound of Formula II where R 22 , R 24 , R 26 , and R 28 are each independently 80
  • TTT may be 81
  • W 501 is –C(O)–, –(CH 2 )ww–, or –(CH 2 )oo–NH2-C(O)–;
  • mm is 0 or 1;
  • ww is 1 or 2;
  • oo is 1 or 2;
  • P 501 , P 502 , and P 503 are each independently H, methyl, benzyl, 4-methoxybenzyl, or tert-butyl. In any embodiment herein, it may be that each of P 501 , P 502 , and P 503 are H.
  • the tripartite compounds of the present technology 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 disclosed herein, any one of the embodiments of the targeting compounds disclosed herein, 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 refered to as “pharmaceutically acceptable carrier” unless otherwise specified).
  • 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 PSMA 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 PSMA or an effective amount of any embodiment of the tripartite compound of the present technology for treating the cancer and/or mammalian tissue overexpressing PSMA.
  • 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 prostate specific membrane antigen (“PSMA”).
  • 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 PSMA 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 PSMA or an effective amount of any embodiment of the tripartite compound of the present technology for treating the cancer and/or mammalian tissue overexpressing PSMA.
  • the subject may suffer from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase (FAP-alpha), or a combination of any two or more thereof and/or mammalian tissue overexpressing PSMA.
  • a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase (FAP-alpha), 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 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 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 glioma e.g., 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
  • an effective amount includes amounts or dosages that are capable of reducing symptoms associated with e.g., one or more of 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, such as, for example, reduction in proliferation and/or metastasis of prostate cancer, breast cancer, or bladder cancer.
  • the effective amount may be 84
  • 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 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 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 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 adenocarcinom
  • 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, any one of the targeting compounds, 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 85
  • compositions described herein may be used to prepare formulations and medicaments that treat e.g., 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.
  • 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.
  • compositions 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.
  • 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, corn 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 (e.g., in a fluorocarbon propellant) aerosols are typically used for delivery of compounds of the present technology by inhalation. 87
  • 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.
  • 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 of any embodiment disclosed herein to a subject having cancer.
  • 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.
  • 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 88
  • the cancer may also be a form of leukemia. In some embodiments, the cancer is a triple negative breast cancer.
  • the dosage of the active ingredient(s) generally depends on the disorder or condition being treated, the extent of the disorder or condition, the method of administration, size of the patient, and potential side effects.
  • 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.
  • composition 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.
  • Hf(IV)-py-macrodipa [00250] A preliminary Hf(IV)-py-macrodipa synthesis involved mixing HfCl4 and adjusting the pH to ⁇ 5 with NaOH, and allowing to stir overnight. A chromatogram (FIG.24) was obtained, evidencing complex formation.
  • Ln 3+ Complexes Stability Constants [00252] Metal complex stability constants provide a quantitative measure of the thermodynamic affinity of ligands for metal ions. The magnitudes of these stability constants for different ligands have been useful for assessing their values in different metal chelation applications.
  • FIG.1 plots log K LnL values against the Ln 3+ 6-coordinate ionic radius 14 for py- macrodipa and macrodipa. Similar to macrodipa, py-macrodipa shows a “dual preference” to Ln 3+ ions: a greater affinity to the large and small Ln 3+ than the middle ones, which strongly suggests that the concept of conformational toggle is preserved in the py-macrodipa system.
  • py-macrodipa shows a great improvement in its affinity to Ln 3+ ions compared to macrodipa, with an about 2-log-unit increase in KLnL for large Ln 3+ and about 1-log-unit rise for small Ln 3+ .
  • Ligand py-macrodipa shows comparable affinity to the largest Ln 3+ ions as does macropa; at the same time, it retains high affinity to the smallest Ln 3+ ions for which macropa barely works.
  • FIG.2 shows stacked 1 H NMR spectra of these complexes.
  • La 3+ , Y 3+ , Lu 3+ , and Sc 3+ show a monotonic decrease in their ionic radius, spanning widely from 103.2 pm to 74.5 pm.
  • La 3+ ⁇ py-macrodipa is present as the 2-fold symmetric Conformation A
  • Lu 3+ Sc 3+ complexes exist as in the asymmetric Conformation B.
  • X-ray crystallography is a characterization method extensively leveraged in coordination chemistry and capable of helping visualize the complexes. 17 To gain more intuitive insights on the structures of Ln 3+ ⁇ py-macrodipa complexes, we characterized three representative Ln 3+ complexes in the series, La 3+ , Lu 3+ , and Sc 3+ , by X-ray crystallography. Their crystal structures are depicted in FIG.3. [00260] These crystal structures are consistent to what has been deduced from the NMR spectroscopy data.
  • La 3+ ⁇ py-macrodipa complex shows a 10-coodinate Conformation A with a slightly distorted C2 symmetry; whereas the Lu 3+ ⁇ and Sc 3+ ⁇ py-macrodipa complexes reside in an 8-coordinate Conformation B without any apparent symmetry elements.
  • the Lu 3+ and Sc 3+ are highly comparable except for a notable difference.
  • one of the ethereal oxygens on the macrocycle takes this 95
  • Lu 3+ crystal was grown via vapor diffusion of Et2O into a MeOH solution, under which condition the H2O source is limited; Sc 3+ crystal was obtained from an aqueous solution instead, a condition that favors H 2 O coordination. Moreover, Lu 3+ ⁇ macrodipa structure represents a Conformation B1, the crystals of which were afforded in an aqueous solution as well.
  • Conformers A and B for all Ln 3+ ⁇ py-macrodipa complexes were optimized and their standard free energies (G°) were calculated.
  • G° standard free energies
  • Conformations B0 and B1 are likely for Conformation B, and thus they both were calculated.
  • the conformational switch between Conformers A and B in the aqueous solution can be written as either Eq 3 or 4, where the standard free energy change of these two reactions are annotated as ⁇ G°(A,B0) and ⁇ G°(A,B1), respectively.
  • FIG.4A summarizes computed ⁇ G°(A,B0) and ⁇ G°(A,B1) values across all Ln 3+ , both of which reveal that large Ln 3+ favors Conformation A and small Ln 3+ prefers Conformation B, complying well with the experimental observations.
  • Conformation B1 is systematically favored over B0 in aqueous solution, by ⁇ 30 kJ ⁇ mol -1 . Since DFT calculation suggests Conformation B1 is more accessible than B0 in aqueous solution, we focus the following calculations particularly on Conformation B1.
  • thermodynamic stability For both ligand systems, the kinetic stability of their Ln 3+ complexes complies with the thermodynamic stability, representing a “high ⁇ low ⁇ high” trend across the series. It should otherwise be clarified that the thermodynamic stability does not necessarily match its kinetic stability in general. In this specific case, this observation can be addressed by the fact that neither of the two conformations is well-suited for middle Ln 3+ ions, and thus their complexes are more labile than Ln 3+ ⁇ py-macrodipa of larger and smaller Ln 3+ .
  • Soc.2020, 142, 13500–13506. (10) Li, L.; Jaraquemada-Peláez, M. de G.; Kuo, H.-T.; Merkens, H.; Choudhary, N.; Gitschtaler, K.; Jermilova, U.; Colpo, N.; Uribe-Munoz, C.; Radchenko, V.; Schaffer, P.; Lin, K.-S.; Bénard, F.; Orvig, C. Functionally Versatile and Highly Stable Chelator for 111 In and 177 Lu: Proof-of-Principle Prostate-Specific Membrane Antigen Targeting. Bioconjugate Chem. 2019, 30, 1539–1553.
  • H2O ⁇ 18 M ⁇ ⁇ cm
  • Organic solvents were of ACS grade or higher. All other reagents were purchased from commercial sources and used without further purification.
  • HPLC High-performance liquid chromatography
  • Method P1 0 ⁇ 10 min, 90% H 2 O/MeOH; 10 ⁇ 25 min, 90% ⁇ 0% H 2 O/MeOH;
  • Method P2 0 ⁇ 15 min, 90% H 2 O/ MeOH ; 15 ⁇ 25 min, 90% ⁇ 0% H 2 O/MeOH.
  • Method P3 0 ⁇ 5 min, 90% H 2 O/MeOH; 5 ⁇ 30 min, 90% ⁇ 0% H 2 O/MeOH. All analytical HPLC runs were carried out with the same method: 0 ⁇ 5 min, 90% H 2 O/MeOH; 5 ⁇ 25 min, 90% ⁇ 0% H 2 O/MeOH.
  • Potentiometric Titrations were carried out using a Metrohm Titrando 888 titrator equipped with a Ross Orion combination electrode (8103BN, ThermoFisher Scientific) and a Metrohm 806 exchange unit with an automatic burette (10 mL). This titration system was controlled by Tiamo (ver.2.5) software. The titration vessel was fitted into a removable glass 108
  • Titration solutions were maintained at a constant ionic strength of 0.1 M with KCl (BioUltra, ⁇ 99.5%, Sigma-Aldrich) and were equilibrated for 15 minutes prior to the addition of titrant.
  • the electrode was calibrated before each titration by titrating a solution of standardized HCl with standardized KOH, and the data were analyzed using the program Glee 5 (ver.3.0.21) to obtain the standard electrode potential and slope factor.
  • Ligand stock solutions were made by dissolving the solid ligand in H 2 O, and their exact concentrations were determined based on the end points of the potentiometric titration curves obtained during the protonation constant determinations.
  • the concentrations determined from titration curves matched the concentrations calculated from the ligand masses, where the MWs of the ligands were estimated from the elemental analysis results.
  • Ln 3+ stock solutions were made by dissolving the corresponding LnCl 3 hydrate salts (99.9% purity or higher) in standardized HCl (0.1 M).
  • the exact concentrations were determined by complexometric titrations 6 with a standardized Na2H2EDTA solution (Alfa Aesar ).
  • Protonation constant or stability constant determinations were carried out by titrating an acidic solution containing free ligand or both ligand and metal with standardized KOH.
  • the ligand concentration was 1 mM.
  • both the ligand and metal ion concentrations were around 1 mM.
  • the total analyte volumes were 15–20 mL. Up to 3 min (protonation constant determinations) or 5 min (stability constant determinations) were given as equilibration times before recording the solution pH after the addition of an aliquot of base.
  • the solutions were inspected throughout the titrations for signs of Ln(OH) 3 precipitation. Data points of the titration curves were excluded from analysis if any precipitate was observed. These titration data were refined with Hyperquad 2013 7 software to determine protonation and stability 109
  • Table 4 provides peak assignments of NMR spectra on La-macrodipa complex. Table 4. Peak assignments of NMR spectra on La-macrodipa complex [00297] Table 5 provides peak assignments of NMR spectra on Lu-macrodipa complex. Table 5. Peak assignments of NMR spectra on Lu-macrodipa complex. 111
  • Table 6 provides peak assignments of NMR spectra on La-macrotripa complex. Table 6. Peak assignments of NMR spectra on La-macrotripa complex. 112
  • Table 7 provides peak assignments of NMR spectra on Lu-macrotripa complex. Table 7. Peak assignments of NMR spectra on Lu-macrotripa complex. 113
  • Hydrogen atoms bound to oxygen were located in the difference Fourier synthesis and subsequently refined semi-freely with the help of distance restraints.
  • the isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the Ueq value of the atoms they are linked to (1.5 times for methyl groups).
  • the La- macrodipa dataset contains disordered solvent molecules of H 2 O that were included in the unit cell but could not be satisfactorily modeled. Therefore, those solvents were treated as diffuse contributions to the overall scattering without specific atom positions using the solvent mask routine in Olex2. 15
  • the Lu-macrodipa stucture was refined as a two-component non-merohedral twin, BASF 0.4739(5).
  • CCDC 2003601 ⁇ 2003603 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: +441223 116
  • Table 8 provides X-ray crystal data and structure refinement details for La- macrodipa ([La(macrodipa)][ClO 4 ] ⁇ DMF), Lu-macrodipa ([Lu(macrodipa)(OH 2 )][PF 6 ] ⁇ 3H2O ) and La-macrotripa ([La(macrotripa)][BPh 4 ] ⁇ Et 2 O ⁇ MeCN) complexes.
  • La- macrodipa [La(macrodipa)][ClO 4 ] ⁇ DMF
  • Lu-macrodipa [Lu(macrodipa)(OH 2 )][PF 6 ] ⁇ 3H2O )
  • La-macrotripa [La(macrotripa)][BPh 4 ] ⁇ Et 2 O ⁇ MeCN) complexes.
  • La-macrodipa [La(macrodipa)][ClO4] ⁇ DMF)
  • Lu-macrodipa [Lu(macrodipa)(OH2)][PF6] ⁇ 3H2O
  • La-macrotripa [La(macrotripa)][BPh 4 ] ⁇ Et 2 O ⁇ MeCN) complexes.
  • FIG.120 shows 1 H NMR spectrum (500 MHz, D2O, pD ⁇ 6, 25 °C) of [La(macrodipa)][ClO 4 ] crystals.
  • FIG.121 shows 1 H NMR spectrum (500 MHz, CD 3 OD, 25 °C) of [Lu(macrodipa)(OH 2 )][PF 6 ] crystals.
  • FIG.122 shows 1 H NMR spectrum (500 MHz, DMSO-d6, 25 °C) of [La(Hmacrotripa)][BPh4] crystals.
  • FIG.124 shows ESI-HRMS of La-macrodipa complex. MeCN was used as the mobile phase.
  • FIG.125 shows ESI-HRMS of Lu-macrodipa complex. MeCN was used as the mobile phase.
  • FIG.126 shows ESI-HRMS of La-macrotripa complex. MeCN was used as the mobile phase.
  • FIG. 127 shows ESI-HRMS of Lu-macrotripa complex. MeCN was used as the mobile phase.
  • DFT Calculations [00308] DFT calculations were executed using Gaussian 09.
  • ⁇ G° value for this conformation switch can be expressed as the sum of three different free energy contributions: relative ligand strain energy ( ⁇ G S °), relative binding energy ( ⁇ G B °), and relative solvation energy ( ⁇ G solv °) between Conf A and Conf B.
  • Ligand strain energy ⁇ G S ° is the standard free energy required to change the free ligand from a fully relaxed conformation to the conformation that is attained when found in the Ln 3+ complex in the gas phase.
  • Binding energy ⁇ G B ° is the standard free energy for the binding process of a Ln 3+ ion to the ligand in the prearranged conformation in the gas phase.
  • Solvation energy ⁇ G solv ° is the standard free energy associated with moving the complexes from the gas phase into aqueous solution.
  • the formula derivation is represented as below. [00312]
  • ⁇ G°(A) G°(A, aq) ⁇ G°(Ln, aq) ⁇ G°(L A , aq).
  • Eqs S5 ⁇ 7 are the solvation processes for involved species.
  • the solvation energies for Ln, L, and LnL A are noted as ⁇ G S °(Ln), ⁇ G S °(L), and ⁇ G S °(A), respectively.
  • Eq S15 can be simplified to Eq S19. It shows the competition between Conf A and Conf B are accounted for by three contributions: ⁇ G S °, ⁇ G B °, and ⁇ G solv °.
  • ⁇ G° ⁇ G S ° + ⁇ G B ° + ⁇ G solv °.
  • S19 [00322] With Eqs S3 and S10, ⁇ GS ° can be obtained by Eq S20. In this case, the unknown G°(L, g) is canceled out.
  • Oxyaapa A Picolinate-Based Ligand with Five Oxygen Donors that Strongly Chelates Lanthanides. Inorg. Chem.2020, 59, 5116–5132.
  • Roca-Sabio A.; Mato-Iglesias, M.; Esteban-Gómez, D.; Tóth, É.; de Blas, A.; Platas- Iglesias, C.; Rodr ⁇ guez-Blas, T. Macrocyclic Receptor Exhibiting Unprecedented Selectivity for Light Lanthanides. J. Am. Chem. Soc.2009, 131, 3331–3341. (10) Gottling, H.
  • Potentiometric titrations were performed to determine their protonation constants (K i , Table 14, FIGs. 41-70). To probe the thermody- namic affinities of these ligands for Ln 3+ ions, we conducted potentiometric titrations to obtain their stability constants (KLnL and KLnHL, Table 13). These protonation and stability constants are defined in eqs 1 ⁇ 3, with the concentrations of all species at chemical equilibrium.
  • FIG.26 shows a plot of log K LnL versus the Ln 3+ ionic radius 28 for both macrodipa and macrotripa, which reveals them to be the first known ligands that exhibit type IV selectivity.
  • log KLnL values between Ln 3+ -macrodipa and Ln 3+ - macrotripa systems they are similar for early lanthanides, La 3+ ⁇ Gd 3+ .
  • Ln 3+ -macrodipa reaches a minimum for Dy 3+ and Ho 3+ , whereas for macrotripa the minimum occurs earlier in the series, between Gd 3+ and Tb 3+ .
  • the macrotripa complexes are significantly more stable than those of macrodipa.
  • the 1 H NMR spectra of all four complexes indicate that a single species is present in solution. However, significant differences are apparent in comparing the La 3+ and Lu 3+ complexes.
  • the La 3+ -macrodipa complex is 2-fold symmetric, indicated by one-half the number of 1 H and 13 C resonances relative to the asymmetric Lu 3+ -macrodipa complex.
  • the hydrogen resonances from the methylene groups linking the crown and picolinate donors H-13, H-20 for macrodipa, and H-13, H-20, H-27 for macrotripa; Scheme 6
  • Scheme 6 which are informative due to their proximities to the picolinate donors, are significantly different between the La 3+ and Lu 3+ complexes.
  • the La 3+ complexes attain a significantly different conformation than do the Lu 3+ complexes.
  • this ion is encapsulated into the 18- membered macrocyclic core, which interacts with all of its six donor atoms.
  • the pendent picolinate groups bind to La 3+ from two opposite faces of the macrocycle, resulting in 10-coordinate complexes.
  • the third picolinate donor of macrotripa does not participate in coordination.
  • [La(macrodipa)] + attains a slightly distorted C2 symmetry.
  • both Lu 3+ structures show significantly different coordination environments.
  • conformations to match the sizes of metal ions accounts for the type IV selectivity pattern.
  • the structures may also explain the difference in thermodynamic stability of macrodipa and macrotripa for the late, but not early, Ln 3+ (FIG.26). Both ligands give rise to identical coordination spheres for the large early lanthanides, like La 3+ , and therefore exhibit only minor differences in their thermodynamic stabilities. However, for the small late lanthanides, like Lu 3+ , the inner coordination spheres are nearly identical between macrodipa and macrotripa, but the outer sphere differs due to the hydrogen-bonding interaction with the coordinated water molecule.
  • thermodynamic stability between the macrodipa and macrotripa complexes of the late lanthanides are most likely a consequence of the hydrogen bonding of the pendent picolinate donor arm. This result highlights how modifying the outer coordination sphere of lanthanide complexes fine-tunes their thermodynamic properties.
  • this conformational toggle we investigated the complexes of Y 3+ , a diamagnetic Ln 3+ analogue with an ionic radius comparable to that of Ho 3+ , 7,28 by NMR spectroscopy.
  • the SMD solvation model 45,46 was implemented to take the solvent effects into consideration.
  • the ⁇ G° for the conformational equilibrium was calculated for Ln 3+ -macrodipa complexes.
  • the ⁇ G° (FIG. 29) is positive for light Ln 3+ and negative for heavy Ln 3+ . This observation is consistent with the experimental results with La 3+ - macrodipa and Lu 3+ -macrodipa complexes attaining Conforma- tions A and B, respectively. Additionally, ⁇ G° changes its sign between Gd 3+ and Tb 3+ , which indicates the switch of favored conformation.
  • ⁇ G° for this conformational change can be broken into three contributors. Specifically, it can be expressed as the sum of the relative ligand strain energies ( ⁇ G S °), relative metal ⁇ ligand binding energies ( ⁇ G B °), and relative solvation energies ( ⁇ Gsolv°) between Conformations A and B. As shown in FIG. 29, ⁇ Gsolv° is positive for all Ln 3+ complexes, which reveals that Conformer A and the noncoordinated water ligand are better solvated in aqueous solution than is Conformer B.
  • ⁇ G B ° is positive for all Ln 3+ , which indicates that Conformation A is better suited to neutralize the electrostatic charges of these ions than is Conformation B.
  • Conformation A interacts with the Ln 3+ with two more donor atoms.
  • ⁇ G B ° decreases as the Ln 3+ gets smaller, which suggests that Conformation A is less effective at binding the smaller ions.
  • ⁇ GS° is negative across the entire series, which shows that Conformation B requires less ligand strain than does Conformation A.
  • ⁇ G S ° shows the most significant changes as a function of the Ln 3+ ionic radius, and it becomes more negative for smaller ions.
  • 225 Ac was produced from irradiated thorium ( 232 Th(p,x) 225/227 Ac ⁇ ), herein referred to as 225/227 Ac ⁇ where the “ ⁇ ” symbol denotes “first-pass 225 Ac”, where separation of 225/227 Ac ⁇ from irradiated thorium was performed as described in Robertson, A. K. H.; McNeil, B. L.; Yang, H.; Gendron, D.; Perron, R.; Radchenko, V.; Zeisler, S.; Causey, P.; Schaffer, P.
  • 213 Bi was eluted with freshly prepared 0.2 M NaI/0.1 M HCl solution (300 ⁇ 600 ⁇ L), wherein the bulk of the activity was eluted in the first 150 ⁇ L. Subsequent elutions (with or without 2 mL of 1 mM HCl prewash of the generator) proceeded no earlier than 3 hours after the last elution, therefore optimizing the ratio of 213 Bi to the amount of other radionuclide impurities such as 209 Pb and 209 Bi.
  • the generator was sealed between each elution to 141 4853-4069-1490.2
  • TLC imaging was performed using an AR-2000 imaging scanner equipped with PD-10 gas, and analysis of RCYs was carried out using WinScan software (ver.3.14).
  • iTLC plate systems are as followed: ⁇ Method A ⁇ macrodipa, py-macrodipa, macropa, and DOTA – paper backed iTLC- silicic acid (iTLC-SA, Agilent Technologies), with EDTA (50 mM, pH 5.5) as mobile 142 4853-4069-1490.2
  • ⁇ Method B ⁇ macrodipa and py-macrodipa – paper backed iTLC-silicic acid (iTLC- SA, Agilent Technologies), with EDTA (50 mM, pH 7) as mobile phase.
  • the macropa and DOTA data are from Fiszbein, D. J.; Brown, V.; Thiele, N. A.; Woods, J. J.; Wharton, L.; MacMillan, S. N.; Radchenko, 143 4853-4069-1490.2
  • Radiochemical yields of approximately 75% and 65% are obtained when using low py-macrodipa concentrations of 10 ⁇ 6 M and 10 ⁇ 8 M for 225 Ac 3+ and 213 Bi 3+ , respectively.
  • py- macrodipa was slightly less effective than macropa, but was better at radiolabeling 213 Bi 3+ .
  • Human Serum Challenge The stability of 225 Ac 3+ ⁇ py-macrodipa and 225 Ac 3+ ⁇ macropa complexes were evaluated in the presence of human serum over a 5-day period.
  • UV–Vis spectra were recorded on a Shimadzu UV-1900 UV ⁇ Vis spectrometer with a 1-cm quartz cuvette.
  • a stock solution of EDTA (150 mM) was prepared in H 2 O, and its pH was adjusted to 5.0 with NMe 4 OH.
  • the concentrations of macrodipa and py-macrodipa were determined by potentiometric titrations, as described in our prior work.
  • the ligand (0.3 ⁇ mol) and metal (0.3 ⁇ mol) were mixed in a cuvette and diluted to 2980 ⁇ L with 0.1 M HOAc/NMe 4 OAc buffer (pH 5.0) to form the complex in situ. After allowing the solution to equilibrate for 15 min, 20 ⁇ L of the EDTA stock solution was added, giving a final complex and EDTA concentrations of 100 ⁇ M and 1 mM, respectively. Upon addition of EDTA, the reaction was monitored immediately by UV–Vis spectroscopy at 25 °C, for up to 5 weeks. The absorbance at 284 nm were plotted as a function of time.
  • H2O ⁇ 18 M ⁇ ⁇ cm
  • Organic solvents were of ACS grade or higher. All other reagents were purchased from commercial sources and used without further purification.
  • the chelator dipy- macrodipa were synthesized following Scheme x.6-Bromomethylpyridine-2-carboxylic methyl ester was prepared as previously described.
  • High-performance liquid chromatography HPLC consisted of a CBM-20A communications bus module, an LC-20AP (preparative) or LC-20AT (analytical) pump, and an SPD-20AV UV ⁇ Vis detector monitoring at 270 nm (Shimadzu, Japan).
  • Method P1 0 ⁇ 20 min, 95% H2O/MeOH; 20 ⁇ 25 min, 95% ⁇ 0% H2O/MeOH; Method P2: 0 ⁇ 10 min, 90% H 2 O/MeOH; 10 ⁇ 50 min, 90% ⁇ 0% H 2 O/MeOH. All analytical HPLC runs were carried out with the same method: 0 ⁇ 5 min, 90% H2O/MeOH; 5 ⁇ 25 min, 90% ⁇ 0% H2O/MeOH. [00355] NMR spectra were acquired on a 500 MHz Bruker AVIII HD spectrometer equipped with a 5 mm, broadband Prodigy cryoprobe operating at 499.76 and 125.68 MHz for 1 H and 13 C observations, respectively.
  • Titration solutions were maintained at a constant ionic strength of 0.1 M with KCl (BioUltra, ⁇ 99.5%, Sigma-Aldrich) and were equilibrated for 15 minutes prior to the addition of titrant.
  • the electrode was calibrated before each titration by titrating a solution of standardized HCl with standardized KOH, and the data were analyzed using the program Glee (ver.3.0.21) to obtain the standard electrode potential and slope factor.
  • Glee ver.3.0.21
  • Ligand stock solutions were made by dissolving the solid ligand in H2O, and their exact concentrations were determined based on the end points of the potentiometric titration curves obtained during the protonation constant measurements. The concentrations determined from titration curves matched the concentrations calculated from the ligand masses using molecular weights obtained from elemental analysis results. Ln 3+ stock solutions were made by dissolving the corresponding LnCl 3 hydrate salts (99.9% purity or 150 4853-4069-1490.2
  • the ligand concentration was 1 mM.
  • both the ligand and metal ion concentrations were around 1 mM.
  • the total analyte volumes were 15–20 mL. Up to 3 min (protonation constant determinations) or 5 min (stability constant determinations) were given as equilibration times before recording the solution pH after the addition of an aliquot of base.
  • the concentrations of dipy-macrodipa and Ln 3+ stock solutions were determined by potentiometric titrations, as described in Section X.
  • the ligand (0.3 ⁇ mol) and metal (0.3 ⁇ mol) were mixed in a cuvette and diluted to 2850 ⁇ L with 0.1 M MOPS buffer (pH 7.4) to form the complex in situ. After allowing the solution to equilibrate for 5 min, 150 ⁇ L of the DTPA stock solution was added, giving a final complex and DTPA concentrations of 100 ⁇ M and 10 mM, respectively.
  • DTPA the concentrations of dipy-macrodipa and Ln 3+ stock solutions were determined by potentiometric titrations, as described in Section X.
  • the ligand (0.3 ⁇ mol) and metal (0.3 ⁇ mol) were mixed in a cuvette and diluted to 2850 ⁇ L with 0.1 M MOPS buffer (pH 7.4) to form the complex in situ. After allowing the solution to
  • reaction mixture was cooled to 0 °C with an ice bath, and NaBH 4 (0.44 g, 11.63 mmol) was slowly added with vigorous stirring.
  • the reaction mixture was stirred at RT overnight.
  • H2O (12 mL) was then added, and the mixture was stirred for another 1.5 h.
  • the MeOH of this mixture was removed under reduced pressure, and the leftover liquid was extracted with 8 ⁇ 30 mL of CH 2 Cl 2 .
  • the combined extractants were dried over Na 2 SO 4 , concentrated to dryness under reduced pressure, and dried under vacuum overnight to afford B (0.80 g, 89%) as a pale-yellow oil.
  • This product had a >95% purity and was used in the next step without further purification.
  • Fmoc- ⁇ -L-alanine (199 mg, 0.64 mmole) was coupled to the resin using PyBOP (167 mg, 0.32 mmole) as coupling reagent in the presence of DIEA (112 ⁇ L, 0.64 mmol) within 12 h.
  • the resin was treated with mixture of 20% piperidine in DMF in order to remove Fmoc group.
  • ⁇ -Ala-PSMA-617 was cleaved from the resin by treatment with a mixture of TFA/TIS/H 2 O (95%/2.5%/2.5%).
  • this reaction mixture is filtered and injected into the preparative HPLC system to purify the product (Method: 0–10 min, 90% H 2 O/MeCN; 10–40 min, 90% ⁇ 0% H 2 O/MeCN). Pure fractions were combined, concentrated under reduced pressure, and lyophilized to yield py- macrodipa-PSMA as white fluffy solid (0.114 g).
  • Radiolabeling of py-macrodipa-PSMA to provide [ 135 La]La–py-macrodipa- PSMA Radio-HPLC analysis was carried out on the Shimadzu HPLC-20AR equipped with a binary gradient, pump, UV–Vis detector, autoinjector and a Laura radiodetector on a Phenomenex Luna (5 ⁇ m, 150 mm x 3 mm, 100 ⁇ ). (HPLC METHOD).
  • 132/135 LaCl 3 was obtained from the Engle Lab at University of Wisconsin-Madison. Py-macrodipa-PSMA (6 ⁇ L, 1 mM, 20% DMSO in 0.5 M NaOAc buffer, pH 5.5) was combined with 132/135 La (537 ⁇ Ci, 66 ⁇ L) and additional NaOAc buffer (320 ⁇ L, 20% DMSO in NaOAc). Quantitative radiolabeling was achieved in 20 min at room temperature and studies were performed without further purification.
  • each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc.
  • all language such as “up to,” “at least,” “greater than,” “less than,” and the like, include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above.
  • a range includes each individual member.
  • a group having 1-3 cells refers to groups having 1, 2, or 3 cells.
  • a group having 1-5 cells refers to groups having 1, 2, 3, 4, or 5 cells, and so forth.
  • a 1 , A 2 , A 3 , and A 4 are each independently R 2 is independently at each occurrence R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); 165 4853-4069-1490.2
  • Y 5 and Y 6 are each independently , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , and Z 13 are independently at each occurrence H or –X 1 –W 2 ;
  • Z 1 is independently at each occurrence OH or NH–W 3 ;
  • Z 9 is independently at each occurrence H, -S(O) 2 OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X 1 –W 2 ;
  • ⁇ is independently at each occurrence 0 or 1;
  • X 1 is independently at each occurrence O, NH, or S;
  • X 2 is independently at each occurrence OH, SH, NH 2 , N(CH 3 )H, or N(CH 3 ) 2 ;
  • X 3 is independently at each occurrence OH, SH,
  • W 2 and W 3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH 2 CH 2 -(OCH 2 CH 2 ) w - R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH 2 CH 2 -(OCH 2 CH 2 ) x -OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH 2 CH 2 -(OCH 2 CH 2 )y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH 2 CH 2 -(OCH 2 CH 2 ) z -OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’,
  • Y 5 and Y 6 are each independently , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , and Z 8 are independently at each occurrence H or –X 1 –W 2 ;
  • Z 1 is independently at each occurrence OH or NH–W 3 ;
  • ⁇ is independently at each occurrence 0 or 1;
  • X 1 is independently at each occurrence O, NH, or S;
  • X 3 is independently at each occurrence OH, SH, NH2, N(CH 3 )H, or N(CH 3 ) 2 ;
  • W 2 and W 3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH 2 CH 2 -(OCH 2 CH 2 )w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH 2 CH 2 -(OCH
  • M 1 is a radionuclide chelated in the compound
  • a 1 , A 2 , A 3 , and A 4 are each independently
  • R 2 is independently at each occurrence
  • R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); 172 4853-4069-1490.2
  • Y 5 and Y 6 are each independently , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , and Z 13 are independently at each occurrence H or –X 1 –W 2 ;
  • Z 1 is independently at each occurrence OH or NH–W 3 ;
  • Z 9 is independently at each occurrence H, -S(O) 2 OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X 1 –W 2 ;
  • ⁇ is independently at each occurrence 0 or 1;
  • X 1 is independently at each occurrence O, NH, or S;
  • X 2 is independently at each occurrence OH, SH, NH 2 , N(CH 3 )H, or N(CH 3 ) 2 ;
  • X 3 is independently at each occurrence OH, SH,
  • W 2 and W 3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH 2 CH 2 -(OCH 2 CH 2 ) w - R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH 2 CH 2 -(OCH 2 CH 2 ) x -OR’ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, -N3, -OR’, -CH 2 CH 2 -(OCH 2 CH 2 )y-R’ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -CH 2 CH 2 -(OCH 2 CH 2 ) z -OR’ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, -SR’, -OC(O)R’, -C(O)OR’,
  • M 1 is a radionuclide chelated in the compound
  • R 2 is independently at each occurrence one of Y 1 and Y 2 is , , , or , and the other one of Y 1 and Y 2 is O
  • one of Y 3 and Y 4 is , , , or , and the other one of Y 3 and Y 4 is O
  • Y 5 and Y 6 are each independently , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , and Z 8 are independently at each occurrence H or –X 1 –W 2 ;
  • Z 1 is independently at each occurrence OH or NH–W 3 ;
  • ⁇ is independently at each occurrence 0 or 1;
  • X 1 is independently at each occurrence O, NH, or S;
  • X 3 is independently at each occurrence OH, SH, NH2, N(CH 3 )H, or N(CH 3 ) 2 ;
  • W 2 and W 3 are each independently at each occurrence H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, -CH 2 CH 2 -(OCH 2 CH 2 )w- R’ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or -CH 2 CH 2 -(OCH
  • Y 5 and Y 6 are each independently , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , and Z 13 are independently at each occurrence H or –X 1 –L 3 –R 22 ;
  • Z 1 is independently at each occurrence OH or NH–L 4 –R 24 ;
  • Z 9 is independently at each occurrence H, -S(O) 2 OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –L 5 –R 26 ;
  • ⁇ is independently at each occurrence 0 or 1;
  • X 1 is independently at each occurrence O, NH, or S;
  • X 2 is independently at each occurrence OH, SH, NH 2 , N(CH 3 )H, or N(CH 3 ) 2 ;
  • X 3 is independently at each
  • L 3 , L 4 , and L 5 are independently at each occurrence a bond or a linker group; and R 22 , R 24 , and R 26 each independently at each occurrence comprise an antibody, antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, a binding polypeptide (such as a selective targeting oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase-containing moiety (such as an oligonucleotide, DNA or RNA vector, or aptamer), or a lectin.
  • the targeting compound of Paragraph H wherein the targeting compound is of any one of Formula V-1, Formula VI-1, and Formula VII-1 or a pharmaceutically acceptable salt and/or solvate thereof, wherein M 1 is a radionuclide chelated in the targeting compound; 182 4853-4069-1490.2
  • Y 5 and Y 6 are each independently , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , and Z 8 are independently at each occurrence H or –X 1 –L 3 –R 22 ;
  • Z 1 is independently at each occurrence OH or NH–L 4 –R 24 ;
  • ⁇ is independently at each occurrence 0 or 1;
  • X 1 is independently at each occurrence O, NH, or S;
  • L 3 , L 4 , and L 5 are independently at each occurrence a bond or a linker group;
  • R 22 , R 24 , and R 26 each independently at each occurrence comprise an antibody, antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, a binding polypeptide (such as a selective targeting oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase-containing moiety (such as an oligonucleo
  • R 22 , R 24 , and R 26 each independently at each occurrence comprise 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,
  • a modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of any one of Formula I, Formula II, Formula III, and Formula IV or pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide, 185 4853-4069-1490.2
  • a 1 , A 2 , A 3 , and A 4 are each independently R 2 is independently at each occurrence R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); one the other one of Y 1 a 2 nd Y is O; 186 4853-4069-1490.2
  • Y 5 and Y 6 are each independently , , , or ; one of Y 7 and Y 8 is , , or , and the other one of Y 7 and Y 8 187 4853-4069-1490.2
  • Y 7 and Y 8 are each independently , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , and Z 13 are independently at each occurrence H or –X 1 –W 2 ;
  • Z 1 is independently at each occurrence OH or NH–W 3 ;
  • Z 9 is independently at each occurrence H, -S(O) 2 OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X 1 –W 2 ;
  • ⁇ is independently at each occurrence 0 or 1;
  • X 1 is independently at each occurrence O, NH, or S;
  • X 2 is independently at each occurrence OH, SH, NH 2 , N(CH 3 )H, or N(CH 3 ) 2 ;
  • X 3 is independently at each occurrence OH, SH,
  • the modified antibody, modified antibody fragment, or modified binding peptide of Paragraph M wherein the compound or pharmaceutically acceptable salt and/or solvate thereof is of any one of Formula I-1, Formula II-1, and Formula III-1 O.
  • the modified antibody, modified antibody fragment, or modified binding peptide of Paragraph M or Paragraph N wherein the antibody comprises belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emtansine
  • PSMA prostate specific membrane antigen
  • Q The modified antibody, modified antibody fragment, or modified binding peptideof any one of any one of Paragraphs M-P, wherein the compound of Formula I is of Formula I-2 or a pharmaceutically acceptable salt and/or solvate thereof.
  • R A modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of any one of Formula IA, Formula IIA, and Formula IIIA or a pharmaceutically acceptable salt and/or solvate thereof, with an antibody, antibody fragment, or binding peptide, 190 4853-4069-1490.2
  • M 1 is a radionuclide chelated in the compound
  • a 1 , A 2 , A 3 , and A 4 are each independently R 2 is independently at each occurrence
  • R 3 and R 4 are each independently H or Z 13 , or R 3 and R 4 together are butylene (e.g., -CH 2 CH 2 CH 2 CH 2 -); one of Y 1 and Y 2 is , , , or , and the other one of Y 1 and Y 2 is O; 191 4853-4069-1490.2
  • Y 5 and Y 6 are each independently , , , or ; one of Y 7 and Y 8 is , , or , and the other one of Y 7 and Y 8 192 4853-4069-1490.2
  • Y 7 and Y 8 are each independently , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , Z 8 , Z 10 , Z 11 , Z 12 , and Z 13 are independently at each occurrence H or –X 1 –W 2 ;
  • Z 1 is independently at each occurrence OH or NH–W 3 ;
  • Z 9 is independently at each occurrence H, -S(O) 2 OH, alkoxy, -S- alkyl, amino, -CN, - OCN, -SCN, -NCO, -NCS, or –X 1 –W 2 ;
  • ⁇ is independently at each occurrence 0 or 1;
  • X 1 is independently at each occurrence O, NH, or S;
  • X 2 is independently at each occurrence OH, SH, NH 2 , N(CH 3 )H, or N(CH 3 ) 2 ;
  • X 3 is independently at each occurrence OH, SH,
  • the modified antibody, modified antibody fragment, or modified binding peptide of Paragraph R wherein the compound or pharmaceutically acceptable salt and/or solvate thereof is of any one of any one of Formula IA-1, Formula IIA-1, and Formula IIIA-1 T.
  • the modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs R-T wherein the antibody comprises belimumab, Mogamulizumab, Blinatumomab, Ibritumomab tiuxetan, Obinutuzumab, Ofatumumab, Rituximab, Inotuzumab ozogamicin, Moxetumomab pasudotox, Brentuximab vedotin, Daratumumab, Ipilimumab, Cetuximab, Necitumumab, Panitumumab, Dinutuximab, Pertuzumab, Trastuzumab, Trastuzumab emt
  • V The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs R-U, wherein the binding peptide comprises a prostate specific membrane antigen (“PSMA”) binding peptide, a somatostatin receptor agonist, a bombesin receptor agonist, a seprase binding compound (e.g., a FAP-alpha binding compound), or a binding fragement thereof.
  • PSMA prostate specific membrane antigen
  • W The modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs R-V, wherein the compound of Formula IA is of Formula IA-2 or a pharmaceutically acceptable salt and/or solvate thereof.
  • X A composition comprising a pharmaceutically acceptable carrier and a compound of any one of Paragraphs A-L. 195 4853-4069-1490.2
  • a composition comprising a pharmaceutically acceptable carrier and a targeting compound of any one of Paragraphs H-L or comprising a pharmaceutically acceptable carrier and a modified antibody, modified antibody fragment, or modified binding peptide of any one of Paragraphs M-W.
  • PSMA prostate specific membrane antigen
  • the pharmaceutical composition of Paragraph Z wherein the pharmaceutical composition comprises an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the compound or an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the modified antibody, modified antibody fragment, or modified binding peptide.
  • AB The pharmaceutical composition of Paragraph Z or Paragraph AA, where the subject suffers from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase, or a combination of any two or more thereof, and/or mammalian tissue overexpressing PSMA.
  • composition of any one of Paragraphs Z-AB 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, a neuroblastoma, AD.
  • any one of Paragraphs Z-AC wherein the subject suffers from one or more of 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 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 adenocarcino
  • AE The pharmaceutical composition of any one of Paragraphs Z-AD, wherein the pharmaceutical composition is formulated for intraveneous administration, optionally comprising sterilized water, Ringer's solution, or an isotonic aqueous saline solution.
  • AF The pharmaceutical composition of any one of Paragraphs Z-AE, 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.
  • AG The pharmaceutical composition of any one of Paragraphs Z-AF, wherein the pharmaceutical composition is provided in an injectable dosage form.
  • AH The pharmaceutical composition of any one of Paragraphs Z-AF, 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 H-L to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of any one Paragraphs M-W.
  • AI comprising administering a targeting compound of any one of Paragraphs H-L to the subject or administering a modified antibody, modified antibody fragment, or modified binding peptide of any one Paragraphs M-W.
  • the method of Paragraph AH wherein the subject suffers from cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”) AJ.
  • PSMA prostate specific membrane antigen
  • the method of Paragraph AH or Paragraph AI wherein the method comprises administering an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the compound or an effective amount for treating the cancer and/or mammalian tissue overexpressing PSMA of the modified antibody, modified antibody fragment, or modified binding peptide AK.
  • any one of Paragraphs AH-AJ wherein the subject suffers from a mammalian tissue expressing a somatostatin receptor, a bombesin receptor, seprase, or a combination of any two or more thereof and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”), when administered to a subject.
  • PSMA prostate specific membrane antigen
  • AL The method of any one of Paragraphs AH-AK, wherein the mammalian tissue comprises 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. 197 4853-4069-1490.2
  • AM The method of any one of Paragraphs AH-AL, wherein the subject suffers from one or more of 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.
  • AN The method of any one of Paragraphs AH-AM, wherein the administering comprises parenteral administration.
  • AO The method of any one of Paragraphs AH-AM, wherein the administering comprises parenteral administration.

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Abstract

La présente invention concerne des composés (comprenant des composés radionucléides chélateurs) ainsi que des compositions comprenant de tels composés utiles dans une radiothérapie ciblée. Par exemple, l'invention concerne un composé de l'une quelconque formule parmi les formule I, formule II, formule III et formule IV ou un sel et/ou un solvate pharmaceutiquement acceptable de celui-ci. L'invention concerne également des équivalents de tels composés.
PCT/US2022/031196 2021-05-26 2022-05-26 Macrocycles et complexes avec des radionucléides utiles dans la radiothérapie ciblée du cancer WO2022251541A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020186328A1 (fr) * 2019-03-20 2020-09-24 The University Of British Columbia Chélateurs et leurs procédés de fabrication et d'utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020186328A1 (fr) * 2019-03-20 2020-09-24 The University Of British Columbia Chélateurs et leurs procédés de fabrication et d'utilisation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE PubChem Substance 4 May 2021 (2021-05-04), "6,6',6''-((1,7,13-Trioxa-4,10,16-triazacyclooctadecane-4,10,16-triyl)tris(methylene))tripicolinic acid", XP093013792, retrieved from ncbi Database accession no. SID 434286317 *
HU AOHAN, ALUICIO-SARDUY EDUARDO, BROWN VICTORIA, MACMILLAN SAMANTHA N., BECKER KAELYN V., BARNHART TODD E., RADCHENKO VALERY, RAM: "Py-Macrodipa: A Janus Chelator Capable of Binding Medicinally Relevant Rare-Earth Radiometals of Disparate Sizes", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, vol. 143, no. 27, 14 July 2021 (2021-07-14), pages 10429 - 10440, XP093013781, ISSN: 0002-7863, DOI: 10.1021/jacs.1c05339 *
HU AOHAN, MACMILLAN SAMANTHA N., WILSON JUSTIN J.: "Macrocyclic Ligands with an Unprecedented Size-Selectivity Pattern for the Lanthanide Ions", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, vol. 142, no. 31, 5 August 2020 (2020-08-05), pages 13500 - 13506, XP093013776, ISSN: 0002-7863, DOI: 10.1021/jacs.0c05217 *

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