Urea-based inhibitors of human glutamate carboxypeptidase II (GCPII) have advanced into clinical trials for imaging metastatic prostate cancer. In parallel efforts, agents with increased lipophilicity have been designed and evaluated for targeting GCPII residing within the neuraxis. Here we report the structural and computational characterization of six complexes between GCPII and P1'-diversified urea-based inhibitors that have the C-terminal glutamate replaced by more hydrophobic moieties. The X-ray structures are complemented by quantum mechanics calculations that provide a quantitative insight into the GCPII/inhibitor interactions. These data can be used for the rational design of novel glutamate-free GCPII inhibitors with tailored physicochemical properties.

Center for Cancer Research Frederick National Laboratory for Cancer Research Macromolecular Crystallography Laboratory Frederick MD 21702 USA

Institute of Biotechnology Academy of Sciences of the Czech Republic v v i Laboratory of Structural Biology Vídeňská 1083 14220 Prague 4 Czech Republic

Russell H Morgan Department of Radiology and Radiological Science Johns Hopkins Medical Institutions 1550 Orleans Street Baltimore MD 21231 USA

Russell H Morgan Department of Radiology and Radiological Science Johns Hopkins Medical Institutions 1550 Orleans Street Baltimore MD 21231 USA; College of Pharmacy Korea University 2511 Sejong ro Sejong 339 700 South Korea

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2-Aminoadipic Acid-C(O)-Glutamate Based Prostate-Specific Membrane Antigen Ligands for Potential Use as Theranostics

Design of composite inhibitors targeting glutamate carboxypeptidase II: the importance of effector functionalities