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 (α-, 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 II:
wherein Z is H, CO 2 H, NH 2 , SH and OH;
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. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of claim 1 , and a pharmaceutically acceptable carrier.
3. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of claim 1 , and at least one or more other biologically active agents.
4. A pharmaceutical composition comprising a compound, salt, solvate, or stereoisomer of claim 1 , and at least one or more other anticancer compounds.
5. 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.