Fap-activated radiotheranostics and uses related thereto

A fibroblast activation protein (FAP)-activated theranostic prodrug represented by the Formula II

• or a pharmaceutically acceptable salt thereof, wherein:
• A represents a 5 to 8 membered heterocyclic ring;
• R10 is R11(C═X)—;
• R11 is —(C1-C10)alkyl, —(C1-C10)alkoxy, —(C1-C10)alkyl-C(O)—OH, —(C1-C10)alkenyl-C(O)—OH, —(C1-C10)alkyl-C(O)—(C1-C10)alkyl, —(C3-C8)cycloalkyl, —(C3-C8)cycloalkyl(C1-C10)alkyl, —(C6-C14)aryl, —(C6-C14)aryl(C1-C10)alkyl, —O—(C1-C4)alkyl-(C6-C14)aryl, 5-10-membered heteroaryl, or 5-10-membered heteroaryl(C1-C10)alkyl, wherein R11 is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, alkoxy, carboxy, cyano, amino, nitro, and thio;
• or R11 is -(AA)n-(C1-C10)alkyl, -(AA)n-(C1-C10)alkoxy, -(AA)n-(C1-C10)alkyl-C(O)—(C1-C10)alkyl, -(AA)n-(C3-C8)cycloalkyl, -(AA)n-(C3-C8)cycloalkyl(C1-C10)alkyl, -(AA)n-(C6-C14)aryl, -(AA)n-(C6-C14)aryl(C1-C10)alkyl, -(AA)n-5-10-membered heteroaryl, or -(AA)n-5-10-membered heteroaryl(C1-C10)alkyl, wherein R11 is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, carboxy, cyano, amino, nitro, and thio;
• R12 is hydrogen or (C1-C6)alkyl;
• R13 is hydrogen, or a (C1-C6)alkyl (which may be straight or branched chain);
• R14 is, independently for each occurrence, —(C1-C6)alkyl, —OH, —NH2, or halogen;
• AA is, independently for each occurrence, an amino acid residue;
• n is an integer from 1 to 5;
• p is an integer from 0-6;
• L is a bond, or after cleavage by FAP to release NH2-L-R, is a self-eliminating linker;
• R is represented by
• TM represents:
• i) etarfolatide, vintafolide, leucovorin and methotrexate;
• ii) octreotate, octreotide, pentetreotide, lanreotide, vapreotide, pasireotide, seglitide, benereotide, KE-108, SDZ-222-100, Sst3-ODN-8, CYN-154806, JR11, J2156, SRA-880, ACQ090, P829, SSTp-58, SSTp-86, BASS or somatoprim;
• iii) cyclo(-Arg-Gly-Asp-D-Phe-Val-) [“c(RGDfV)” ], c(RGDfK), c(RGDfC), c(RADfC), c(RADfK), c(RGDfE), c(RADfE), RGDSK, RADSK, RGDS, c(RGDyC), c(RADyC), c(RGDyE), c(RGDyK), c(RADyK), H-E[c(RGDyK)]2, EMD 12194, DMP728, DMP757 and SK&F107260;
• L1 represents a bond or a linker;
• and
• R20 represents a chelating agent.

A fibroblast activation protein (FAP)-activated theranostic prodrug, represented by Formula VII:

• or a pharmaceutically acceptable salt thereof, wherein:
• R is a ligand-targeted theranostic moiety, including a ligand for binding to a cellular target and a chelating agent for chelating a radioactive moiety;
• R11 is —(C1-C10)alkyl, —(C1-C10)alkoxy, —(C1-C10)alkyl-C(O)—OH, —(C1-C10)alkenyl-C(O)—OH, —(C1-C10)alkyl-C(O)—(C1-C10)alkyl, —(C3-C8)cycloalkyl, —(C3-C8)cycloalkyl(C1-C10)alkyl, —(C6-C14)aryl, —(C6-C14)aryl(C1-C10)alkyl, —O—(C1-C4)alkyl-(C6-C14)aryl, 5-10-membered heteroaryl, or 5-10-membered heteroaryl(C1-C10)alkyl, wherein R11 is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxy, alkoxy, carboxy, cyano, amino, nitro, and thio;
• and
• L is a bond, or after cleavage by FAP to release NH2-L-R, is a self-eliminating linker.