Bivalent Inhibitors of Prostate-Specific Membrane Antigen Conjugated to Desferrioxamine B Squaramide Labeled with Zirconium-89 or Gallium-68 for Diagnostic Imaging of Prostate Cancer
Asif Noor, Jessica Van Zuylekom, Stacey E. Rudd, Kelly Waldeck, Peter Roselt, Mohammad B. Haskali, Michael Wheatcroft, Eddie Yan, Rodney J. Hicks, Carleen Cullinane, Paul S. Donnelly
Abstract
Prostate-specific membrane antigen (PSMA) is a carboxypeptidase that is overexpressed in prostate cancer and is an excellent candidate for targeted diagnostic imaging and therapy. Lysine-ureido-glutamate inhibitors of PSMA radiolabeled with positron-emitting radionuclides can be used for diagnostic imaging with positron emission tomography (PET). A squaramide ester derivative of desferrioxamine B (H3DFOSq) was used to prepare four new agents with either one or two lysine-ureido-glutamate pharmacophores. The H3DFOSq ligand can be used to form stable complexes with either of the positron-emitting radionuclides gallium-68 (t1/2 = 68 min) or zirconium-89 (t1/2 = 3.3 days). The complexes were evaluated in PSMA-positive xenograft mouse models. Bivalent inhibitors, where two pharmacophores are tethered to a single DFOSq ligand, have better tumor uptake than their monovalent analogues. The ligands presented here, which can be labeled with either gallium-68 or zirconium-89, have the potential to increase the number of clinical sites that can perform diagnostic PET imaging.