Cholecystokinin B receptor targeting for imaging and therapy
Conjugates are described herein where CCK2R targeting ligands are attached to an active moiety, such as therapeutic agent or an imaging agent, through a linker. The conjugates can be used in the detection, diagnosis, imaging and treatment of cancer.
1. A conjugate of the formula
B-L-D
wherein
B is a targeting ligand of Formula I
L is a bivalent or polyvalent linker; and
D is an optical dye; or a pharmaceutically acceptable salt thereof.
2. The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the optical dye is of Formula II
wherein
X is selected from the group consisting of oxygen, nitrogen, and sulfur, and X is attached to the linker L;
Y is selected from the group consisting of OR a , NR a 2 , and NRa 3 + ;
Y′ is selected from the group consisting of O, NR a , and NR a 2 + ;
each R is independently selected from the group consisting of H, fluoro, sulfonic acid, sulfonate, and salts thereof; and
R a is hydrogen or alkyl.
3. The conjugate of claim 2 , or a pharmaceutically acceptable salt thereof, wherein X is nitrogen.
4. The conjugate of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R is H.
5. The conjugate of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R a is hydrogen.
6. The conjugate of claim 2 , or a pharmaceutically acceptable salt thereof, wherein Y′ is O.
7. The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the optical dye is of Formula III
wherein X is selected from the group consisting of oxygen, nitrogen, and sulfur, and X is attached to linker L.
8. The conjugate of claim 7 , or a pharmaceutically acceptable salt thereof, wherein X is nitrogen.
9. The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the optical dye is selected from the group consisting of fluorescein (FITC), rhodamine, S0456, IR800CW, and LS288.
10. The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker L is a non-releasable linker.
11. The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker L comprises one or more amino acids.
12. The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker L comprises glutamic acid.
13. The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker L comprises a carbamate moiety.
14. The conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker L is L1, L2 or L3
L1: HN-Glu-Arg-Asp-CO
L2: HN-Glu-PS-Glu-PS-CO
L3: HN-Octanoyl-Glu-PS-Glu-PS-CO
wherein PS is of the formula
15. A conjugate of the formula