Compounds and radioligands for targeting neurotensin receptor and uses thereof

A radionuclide complex comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, and one or more radionuclides:

• wherein
• R1 is selected from H, C1-6alkyl, C3-6cycloalkyl and C1-3alkyleneC3-6cycloalkyl, the latter three groups being optionally substituted with one or more halo;
• R2 is selected from H, halo, NO2, C1-6alkyl, C3-8cycloalkyl and C1-3alkyleneC3-8cycloalkyl, the latter three groups being optionally substituted with one or more halo;
• R3 is selected from 2-amino-2-adamantane carboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid;
• X is O;
• L consists of 1 to 10 groups independently selected from C1-6alkyleneO, C1-6alkyleneNR7, C(O)C1-6alkyleneO and C(O)C1-6alkyleneNR7, wherein R7 is H or C1-4alkyl;
• E is selected from the group consisting of 1,4,7-triazacyclononane (TACN);
• 1,4,7-triazacyclononane-triacetic acid (NOTA);
• 1,4,7-triazacyclononane-N-succinic acid-N′,N″-diacetic acid (NOTASA);
• 1,4,7-triazacyclononane-N-glutamic acid-N′,N″-diacetic acid (NODAGA);
• 1,4,7-triazacyclononane-N,N′,N″-tris(methylenephosphonic) acid (NOTP);
• 1,4,7,10-tetraazacyclododecane ([12]aneN4) (cyclen);
• 1,4,7,10-tetraazacyclotridecane ([13]aneN4);
• 1,4,7,11-tetraazacyclotetradecane (iso-cyclam);
• 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA);
• 2-(1,4,7,10-tetraazacyclododecan-1-yl)acetate (DO1A);
• 2,2′-(1,4,7,10-tetraazacyclododecane-1,7-diyl) diacetic acid (DO2A);
• 2,2′,2″-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (DO3A);
• 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methanepnosphonic acid) (DOTP);
• 1,4,7,10-tetraazacyclododecane-1,7-di(methanephosphoriic acid) (DO2P);
• 1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid) (DO3P);
• 1,4,7,10-tetraazacyclo-decane-1-glutamic acid-4,7,10-triacetic acid (DOTAGA);
• 1,4,7,10-tetraazacyclodecane-1-succinic acid-4,7,10-triacetic acid (DOTASA);
• 1,4,8,11-tetraazacyclotetradecane ([14]aneN4) (cyclam);
• 1,4,8,12-tetraazacyclopentadecane ([15]aneN4);
• 1,5,9,13-tetraazacyclohexadecane ([16]aneN4);
• 1,4-ethano-1,4,8,11-tetraazacyclo-tetradecane (et-cyclam);
• 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA);
• 2-(1,4,8,11-tetraazacyclotetradecane-1-yl) acetic acid (TE1A);
• 2,2′-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl) diacetic acid (TE2A);
• 4,11-bis(carboxy methyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane (CB-TE2A);
• 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane (Sar);
• 1,4,7,10-tetra-(2-carbamoyl-methyl)-cyclododecane (TCMC);
• N,N′-bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6 (macropa), phthalocyanines, and porphyrins.

A radionuclide complex comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, and one or more radionuclides:

• wherein
• R1 is selected from H, C1-6alkyl, C3-6cycloalkyl and C1-3alkyleneC3-6cycloalkyl, the latter three groups being optionally substituted with one or more halo;
• R2 is selected from H, halo, NO2, C1-6alkyl, C3-8cycloalkyl and C1-3alkyleneC3-8cycloalkyl, the latter three groups being optionally substituted with one or more halo;
• R3 is selected from 2-amino-2-adamantane carboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid;
• X is NR4, or NR4C(O);
• L consists of 1 to 10 groups independently selected from C1-6alkyleneO, C1-6alkyleneNR7, C(O)C1-6alkyleneO and C(O)C1-6alkyleneNR7, wherein R7 is H or C1-4alkyl;
• E is selected from the group consisting of 1,4,7-triazacyclononane (TACN);
• 1,4,7-triazacyclononane-triacetic acid (NOTA);
• 1,4,7-triazacyclononane-N-succinic acid-N′,N″-diacetic acid (NOTASA);
• 1,4,7-triazacyclononane-N-glutamic acid-N′,N″-diacetic acid (NODAGA);
• 1,4,7-triazacyclononane-N,N′,N″-tris(methylenephosphonic) acid (NOTP);
• 1,4,7,10-tetraazacyclododecane ([12]aneN4) (cyclen);
• 1,4,7,10-tetraazacyclotridecane ([13]aneN4);
• 1,4,7,11-tetraazacyclotetradecane (iso-cyclam);
• 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA);
• 2-(1,4,7,10-tetraazacyclododecan-1-yl)acetate (DO1A);
• 2,2′-(1,4,7,10-tetraazacyclododecane-1,7-diyl) diacetic acid (DO2A);
• 2,2′,2″-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (DO3A);
• 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methanepnosphonic acid) (DOTP);
• 1,4,7,10-tetraazacyclododecane-1,7-di(methanephosphoriic acid) (DO2P);
• 1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid) (DO3P);
• 1,4,7,10-tetraazacyclo-decane-1-glutamic acid-4,7,10-triacetic acid (DOTAGA);
• 1,4,7,10-tetraazacyclodecane-1-succinic acid-4,7,10-triacetic acid (DOTASA);
• 1,4,8,11-tetraazacyclotetradecane ([14]aneN4) (cyclam);
• 1,4,8,12-tetraazacyclopentadecane ([15]aneN4);
• 1,5,9,13-tetraazacyclohexadecane ([16]aneN4);
• 1,4-ethano-1,4,8,11-tetraazacyclo-tetradecane (et-cyclam);
• 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA);
• 2-(1,4,8,11-tetraazacyclotetradecane-1-yl) acetic acid (TE1A);
• 2,2′-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl) diacetic acid (TE2A);
• 4,11-bis(carboxy methyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane (CB-TE2A);
• 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane (Sar);
• 1,4,7,10-tetra-(2-carbamoyl-methyl)-cyclododecane (TCMC);
• N,N′-bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6 (macropa), phthalocyanines, and porphyrins;
• R4 is selected from H, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C(O)C1-6alkyl, C1-10alkyleneNR5R6, C1-10alkenyleneNR5R6, and C1-10alkynyleneNR5R6;
• and
• R5 and R6 are independently selected from H and C1-6alkyl.

A radionuclide complex comprising a compound of Formula I or a pharmaceutically acceptable salt or solvate thereof, and one or more radionuclides:

• wherein
• R1 is selected from H, C1-6alkyl, C3-6cycloalkyl and C1-3alkyleneC3-6cycloalkyl, the latter three groups being optionally substituted with one or more halo;
• R2 is selected from H, halo, NO2, C1-6alkyl, C3-8cycloalkyl and C1-3alkyleneC3-8cycloalkyl, the latter three groups being optionally substituted with one or more halo;
• R3 is selected from 2-amino-2-adamantane carboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid;
• X is CH2, S, S(O), or SO2NR4;
• L consists of 1 to 10 groups independently selected from C1-6alkyleneO, C1-6alkyleneNR7, C(O)C1-6alkyleneO and C(O)C1-6alkyleneNR7, wherein R7 is H or C1-4alkyl;
• E is selected from the group consisting of 1,4,7-triazacyclononane (TACN);
• 1,4,7-triazacyclononane-triacetic acid (NOTA);
• 1,4,7-triazacyclononane-N-succinic acid-N′,N″-diacetic acid (NOTASA);
• 1,4,7-triazacyclononane-N-glutamic acid-N′,N″-diacetic acid (NODAGA);
• 1,4,7-triazacyclononane-N,N′,N″-tris(methylenephosphonic) acid (NOTP);
• 1,4,7,10-tetraazacyclododecane ([12]aneN4) (cyclen);
• 1,4,7,10-tetraazacyclotridecane ([13]aneN4);
• 1,4,7,11-tetraazacyclotetradecane (iso-cyclam);
• 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA);
• 2-(1,4,7,10-tetraazacyclododecan-1-yl)acetate (DO1A);
• 2,2′-(1,4,7,10-tetraazacyclododecane-1,7-diyl) diacetic acid (DO2A);
• 2,2′,2″-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (DO3A);
• 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methanepnosphonic acid) (DOTP);
• 1,4,7,10-tetraazacyclododecane-1,7-di(methanephosphoriic acid) (DO2P);
• 1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid) (DO3P);
• 1,4,7,10-tetraazacyclo-decane-1-glutamic acid-4,7,10-triacetic acid (DOTAGA);
• 1,4,7,10-tetraazacyclodecane-1-succinic acid-4,7,10-triacetic acid (DOTASA);
• 1,4,8,11-tetraazacyclotetradecane ([14]aneN4) (cyclam);
• 1,4,8,12-tetraazacyclopentadecane ([15]aneN4);
• 1,5,9,13-tetraazacyclohexadecane ([16]aneN4);
• 1,4-ethano-1,4,8,11-tetraazacyclo-tetradecane (et-cyclam);
• 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA);
• 2-(1,4,8,11-tetraazacyclotetradecane-1-yl) acetic acid (TE1A);
• 2,2′-(1,4,8,11-tetraazacyclotetradecane-1,8-diyl) diacetic acid (TE2A);
• 4,11-bis(carboxy methyl)-1,4,8,11-tetraazabicyclo[6.6.2]-hexadecane (CB-TE2A);
• 3,6,10,13,16,19-hexaazabicyclo[6.6.6]icosane (Sar);
• 1,4,7,10-tetra-(2-carbamoyl-methyl)-cyclododecane (TCMC);
• N,N′-bis[(6-carboxy-2-pyridil)methyl]-4,13-diaza-18-crown-6 (macropa), phthalocyanines, and porphyrins;
• R4 is selected from H, C1-6alkyl, C1-6alkenyl, C1-6alkynyl, C(O)C1-6alkyl, C1-10alkyleneNR5R6, C1-10alkenyleneNR5R6, and C1-10alkynyleneNR5R6;
• and
• R5 and R6 are independently selected from H and C1-6alkyl.