Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 63, Issue 17, Pages 9258-9270Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00291
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Funding
- National Health and Medical Research Council, Australia
- Australian Cancer Research Foundation
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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 (H(3)DFOSq) was used to prepare four new agents with either one or two lysine-ureido-glutamate pharmacophores. The H(3)DFOSq ligand can be used to form stable complexes with either of the positron-emitting radionuclides gallium-68 (t(1/2) = 68 min) or zirconium-89 (t(1/2) = 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.
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