Macrocyclic complexes of alpha-emitting radionuclides and their use in targeted radiotherapy of cancer
AssigneeCornell University
InventorsJohn W. Babich, Justin WILSON, Nikki THIELE, James KELLY, Shashikanth PONNALA
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Abstract
The present technology provides compounds as well as compositions including such compounds useful in targeted radiotherapy of cancer and/or mammalian tissue overexpressing prostate specific membrane antigen (“PSMA”) where the compounds are represented by the following: or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, wherein M1 is independently at each occurrence an alpha-emitting radionuclide. Equivalents of such compounds are also disclosed.
Claims23
A modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula I or Formula IA
- or a pharmaceutically acceptable salt thereof, with an antibody, antibody fragment, or binding peptide, wherein
- M1 is an alpha-emitting radionuclide;
- Z1 is H or —X1—W2;
- Z2 is OH or NH—W3;
- Z3 is H or W7;
- α is 0 or 1;
- X1 is O, NH, or S;
- W2 and W3 are each independently H, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, —CH2CH2—(OCH2CH2)w—R′ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or —CH2CH2—(OCH2CH2)x—OR′ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, —N3, —OR′, —CH2CH2—(OCH2CH2)y—R′ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, —CH2CH2—(OCH2CH2)z—OR′ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, —SR′, —OC(O)R′, —C(O)OR′, —C(S)OR′, —S(O)R′, —SO2R′, —SO2(OR′), —SO2NR′2, —P(O)(OR′)2, —P(O)R′(OR′), —P(O)R′2, —CN, —OCN, —SCN, —NCO, —NCS, —NR′—NH2, —N═C═N—R′, —SO2Cl, —C(O)Cl, or an epoxide group;
- W5 and W7 are each independently OH, NH2, SH, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, —CH2CH2—(OCH2CH2)w—R′ where w is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, or —CH2CH2—(OCH2CH2)x—OR′ where x is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, each of which may optionally be substituted with one or more of halo, —N3, —OR′, —CH2CH2—(OCH2CH2)yx—R′ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, —CH2CH2—(OCH2CH2)z—OR′ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, —SR′, —OC(O)R′, —C(O)OR′, —C(S)OR′, —S(O)R′, —SO2R′, —SO2(OR′), —SO2NR′2, —P(O)(OR′)2, —P(O)R′(OR′), —P(O)R′2, —CN, —OCN, —SCN, —NCO, —NCS, —NR′—NH2, —N═C═N—R′, —SO2Cl, —C(O)Cl, or an epoxide group;
- and
- R′ is independently at each occurrence H, halo, —N3, C1-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C5-C8cycloalkenyl, C2-C6 alkynyl, C5-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl.
Dependencies are inferred from the claim text.