Macrocyclic complexes of radionuclides and their use in radiotherapy of cancer

A compound of Formula IA

• or a pharmaceutically acceptable salt thereof, 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, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl.

A targeting compound of Formula II

• or a pharmaceutically acceptable salt thereof, wherein
• M1 is an alpha-emitting radionuclide;
• Z1 is H or -L3-R22
• Z2 is OH or NH-L4-R24
• Z3 is H or -L6-R28;
• α is 0 or 1;
• X1 is O, NH, or S;
• L3, L4, L5, and L6 are independently at each occurrence a bond or a linker group;
• and
• R22, R24, R26, and R28 each independently comprises 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.

A modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of Formula I

• or pharmaceutically acceptable salt thereof, with an antibody, antibody fragment, or binding peptide, wherein
• 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)x—R′ where y is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, —CH2CH2—(OCH2CH2)z—OR′ where z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, —SR′, —OC(O)R′, —C(O)OR′, —C(S)OR′, —S(O)R′, —SO2R′, —SO2(OR′), —SO2NR′2, —P(O)(OR′)2, —P(O)R′(OR′), —P(O)R′2, —CN, —OCN, —SCN, —NCO, —NCS, —NR′—NH2, —N═C═N—R′, —SO2Cl, —C(O)Cl, or 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, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl.

A modified antibody, modified antibody fragment, or modified binding peptide comprising a linkage arising from conjugation of a compound of 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—R′ 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—R′ 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, C8-C10 cycloalkynyl, C5-C6 aryl, heterocyclyl, or heteroaryl.