Antibodies for chelated radionuclides and clearing agents

A clearing agent comprising dextran or an aminodextran conjugated to a chelating agent selected from DOTAM and a functional variant of DOTAM, wherein said chelating agent is complexed with a metal ion, and said functional variant of DOTAM is according to the following formula:

• or a pharmaceutically acceptable salt thereof;
• wherein
• RN is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-4 alkyl, phenyl, phenyl-C1-4-alkyl, C1-7 heteroaryl, and C1-7 heteroaryl-C1-4-alkyl;
• wherein C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected Rw groups;
• and wherein said C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-4 alkyl, phenyl, phenyl-C1-4-alkyl, C1-7 heteroaryl, and C1-7 heteroaryl-C1-4-alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected Rx groups;
• L1 is independently C1-6 alkylene, C1-6 alkenylene, or C1-6 alkynylene, each of which is optionally substituted by 1, 2, or 3 groups independently selected R1 groups;
• L2 is C2-4 straight chain alkylene, which is optionally substituted by an independently selected R1 group;
• and which is optionally substituted by 1, 2, 3, or 4 groups independently selected from C1-4 alkyl and or C1-4 haloalkyl;
• R1 is independently selected from D1-D2-D3, halogen, cyano, nitro, hydroxyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, amino, C1-6 alkylamino, di-C1-6 alkylamino, C1-4 alkylcarbonyl, carboxy, C1-6 alkoxycarbonyl, C1-6 alkylcarbonylamino, di-C1-6 alkylcarbonylamino, C1-6 alkoxycarbonylamino, C1-6 alkoxycarbonyl-(C1-6 alkyl)amino, carbamyl, C1-6 alkylcarbamyl, and di-C1-6 alkylcarbamyl;
• each D1 is independently selected from C6-10 aryl-C1-4 alkyl, C1-9 heteroaryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, C2-9 heterocycloalkyl-C1-4 alkyl, C1-8 alkylene, C1-8 alkenylene, and C1-8 alkynylene;
• wherein said C1-8 alkylene, C1-8 alkenylene, and C1-8 alkynylene are optionally substituted by 1, 2, 3, or 4 independently selected R4 groups;
• and wherein said C6-10 aryl-C1-4 alkyl, C1-9 heteroaryl-C1-4 alkyl, C3-10 cycloalkyl-C1-4 alkyl, C2-9 heterocycloalkyl-C1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R5 groups;
• each D2 is independently absent or C1-20 straight chain alkylene, wherein from 1 to 6 non-adjacent methylene groups of said C1-20 straight chain alkylene are each optionally replaced by an independently selected -D4- moiety, provided that at least one methylene unit in said C1-20 straight chain alkylene is not optionally replaced by a -D4- moiety;
• wherein said C1-20 straight chain alkylene is optionally substituted by one or more groups independently selected from halogen, cyano, nitro, hydroxyl, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, di-C1-4 alkylamino, C1-4 alkylcarbonyl, carboxy, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, di-C1-4 alkylcarbonylamino, C1-4 alkoxycarbonylamino, C1-4 alkoxycarbonyl-(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, and di-C1-4 alkylcarbamyl;
• each D3 is independently selected from H, halogen, cyano, nitro, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-14 cycloalkyl, C3-14 cycloalkyl-C1-4 alkyl, C2-14 heterocycloalkyl, C2-14 heterocycloalkyl-C1-4 alkyl, C6-14 aryl, C6-14 aryl-C1-4 alkyl, C1-13 heteroaryl, C1-13 heteroaryl-C1-4 alkyl;
• wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R6 groups;
• and wherein said C3-14 cycloalkyl, C3-14 cycloalkyl-C1-4 alkyl, C2-14 heterocycloalkyl, C2-14 heterocycloalkyl-C1-4 alkyl, C6-14 aryl, C6-14 aryl-C1-4 alkyl, C1-13 heteroaryl, C1-13 heteroaryl-C1-4 alkyl are each optionally substituted by 1, 2, 3 or 4 independently selected R7 groups;
• each D4 is independently selected from —O—, —S—, —NRaC(═O)—, —NRaC(═S)—, —NRbC(═O)NRc—, —NRbC(═S)NRc—, —S(═O)—, —S(═O)2—, —S(═O)NRa—, —C(═O)—, —C(═S)—, —C(═O)O—, —OC(═O)NRa—, —OC(═S)NRa—, —NRa—, —NRbS(═O)NRc—, and NRbS(═O)2NRO—;
• each R4 and R6 is independently selected from halogen, cyano, nitro, hydroxyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, amino, C1-4 alkylamino, di-C1-4 alkylamino, C1-4 alkylcarbonyl, carboxy, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, di-C1-4 alkylcarbonylamino, C1-4 alkoxycarbonylamino, C1-4 alkoxycarbonyl-(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, and di-C1-4 alkylcarbamyl;
• each R5 is independently selected from halogen, cyano, cyanate, isothiocyanate, nitro, hydroxyl, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, C1-4 alkylsulfonyl, amino, C1-4 alkylamino, di-C1-4 alkylamino, C1-4 alkylcarbonyl, carboxy, C1-4 alkoxycarbonyl, C1-4 alkylcarbonylamino, di-C1-4 alkylcarbonylamino, C1-4 alkoxycarbonylamino, C1-4 alkoxycarbonyl-(C1-4 alkyl)amino, carbamyl, C1-4 alkylcarbamyl, and di-C1-4 alkylcarbamyl;
• each R7 is independently selected from halogen, cyano, nitro, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-4 alkyl, phenyl, phenyl-C1-4 alkyl, C1-7 heteroaryl, C1-7 heteroaryl-C1-4 alkyl, —ORO, —SRO, —S(═O)RP, —S(═O)2RP, —S(═O)NRsRt, —C(═O)RP, —C(═O)ORP, —C(═O)NRsRt, —OC(═O)RP, —OC(═O)NRsRt, —NRsRt, —NRqC(═O)Rr, —NRqC(═O)ORr, —NRqC(═O)NRr, —NRqS(═O)2Rr, and —NRPS(═O)2NRsRt;
• wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected R′ groups;
• and wherein said C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-4 alkyl, phenyl, phenyl-C1-4 alkyl, C1-7 heteroaryl, C1-7 heteroaryl-C1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R″ groups;
• each Ra, Rb, and Rc is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-4 alkyl, phenyl, phenyl-C1-4 alkyl, C1-7 heteroaryl, C1-7 heteroaryl-C1-4 alkyl;
• wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected Rw groups;
• and wherein said C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C2-7 heterocycloalkyl,
• C2-7 heterocycloalkyl-C1-4 alkyl, phenyl, phenyl-C1-4 alkyl,
• C1-7 heteroaryl, C1-7 heteroaryl-C1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected Rx groups;
• each Ro, Rp, Rq, Rr, Rs and Rt is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-4 alkyl, phenyl, phenyl-C1-4 alkyl, C1-7 heteroaryl, C1-7 heteroaryl-C1-4 alkyl;
• wherein said C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl are each optionally substituted by 1, 2, 3, or 4 independently selected Ry groups;
• and wherein said C3-7 cycloalkyl, C3-7 cycloalkyl-C1-4 alkyl, C2-7 heterocycloalkyl, C2-7 heterocycloalkyl-C1-4 alkyl, phenyl, phenyl-C1-4 alkyl, C1-7 heteroaryl, C1-7 heteroaryl-C1-4 alkyl are each optionally substituted by 1, 2, 3, or 4 independently selected Rz groups;
• each R′, Rw and Ry is independently selected from hydroxyl, cyano, nitro, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, and di-C1-4 alkylamino;
• and
• each R″, Rx, and Rz is independently selected from hydroxyl, halogen, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, and di-C1-4 alkylamino;
• provided that the valency of each atom in the optionally substituted moieties is not exceeded.