Homomultivalent and heteromultivalent inhibitors of prostate specific membrane antigen (PSMA) and uses thereof
The present invention provides bivalent and multivalent ligands with a view to improving the affinity and pharmacokinetic properties of a urea class of PSMA inhibitors. The compounds and their synthesis can be generalized to multivalent compounds of other target antigens. Because they present multiple copies of the pharmacophore, multivalent ligands can bind to receptors with high avidity and affinity, thereby serving as powerful inhibitors. The modular multivalent scaffolds of the present invention, in one or more embodiments, contains a lysine-based (∝, ε-) dialkyne residue for incorporating two or more antigen binding moieties, such as PSMA binding Lys-Glu urea moieties, exploiting click chemistry and one or more additional lysine residues for subsequent modification with an imaging and/or therapeutic nuclides or a cytotoxic ligands for tumor cell killing.
1. A compound of formula I:
wherein Z is H, CO 2 H, NH 2 , SH or OH;
wherein m is 2 to 16;
wherein R 1 is the same or different moiety and is selected from the group consisting of:
and
alternatively, R 1 is a peptide ligand to an enzyme or endothelial receptor; and
wherein R 2 is a chelating moiety, a fluorescent dye or H,
wherein when R 2 is a chelating moiety, it can be bound to a metal ion useful in imaging, or as a cytotoxic moiety; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
2. The compound of claim, wherein the compound is compound of formula VI:
wherein R 1 is the same or different moiety and is selected from the group consisting of:
and
alternatively, R 1 is a peptide ligand to an enzyme or endothelial receptor; and
wherein R 2 is a chelating moiety, a fluorescent dye or H,
wherein when R 2 is a chelating moiety, it can be bound to a metal ion useful in imaging, or as a cytotoxic moiety; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
3. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of claim 1 , and a pharmaceutically acceptable carrier.
4. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of claim 1 , and at least one or more other biologically active agents.
5. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of claim 1 , and at least one or more other anticancer compounds.
6. A method of imaging prostate cancer in a subject comprising administering to the subject an effective amount of a compound, salt, solvate, or stereoisomer of claim 1 , or pharmaceutical compositions thereof, wherein R 2 is chelating moiety bound to a metal ion useful in imaging, or fluorescent dye and detecting the prostate by use of PET or SPECT.
7. A compound of formula (XI):
wherein M 3+ is a metal ion useful in imaging or radiotherapy;
or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
8. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of claim 7 , and a pharmaceutically acceptable carrier.
9. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of claim 7 , and at least one or more other biologically active agent.
10. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of claim 7 , and at least one or more other anticancer compound.
11. A method of treating cancer in a subject comprising administering to the subject an effective amount of a compound, salt, solvate, or stereoisomer of claim 7 and wherein the metal ion is useful in radiotherapy.
12. The method of claim 11 , wherein the cancer is prostate cancer.
13. A method of imaging prostate cancer in a subject comprising administering to the subject an effective amount of a compound, salt, solvate, or stereoisomer of claim 7 , or pharmaceutical compositions thereof and detecting the prostate by use of PET or SPECT.