title: Synthesis and evaluation of constrained phosphoramidate inhibitors of prostate-specific membrane antigen.
abstract: Prostate-specific membrane antigen (PSMA) is a cell-surface enzyme-biomarker that is actively pursued for targeted delivery of imaging and therapeutic agents for prostate cancer. Our lab has developed PSMA inhibitors based on a phosphoramidate scaffold, which has shown both high selectivity for PSMA-positive tumors and rapid clearance in vivo when radiolabeled with (18)F. However, this scaffold exhibits hydrolytic instability under low pH and high temperature conditions, barring the use of other imaging or therapeutic radionuclides such as (68)Ga or (177)Lu. Previous studies in our lab have shown a trend in increasing acid stability as the distance between the phosphoramidate core and the α-carboxylate of the P1 residue is increased. Therefore, a new generation of phosphoramidate inhibitors was developed based on trans-4-hydroxyproline as the P1 residue to restrict the interaction of the α-carboxylate to the phosphoramidate core. These hydroxyproline inhibitors demonstrated comparable IC50 values to earlier generations as well as enhanced thermal and acid stability.
authors.affiliation: Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA.
authors.forename: Corinne R
authors.initials: CR
authors.lastname: Ley
authors.affiliation: Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Beattie
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94158, USA.
authors.forename: Shorouk
authors.initials: S
authors.lastname: Dannoon
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94158, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Regan
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94158, USA.
authors.forename: Henry
authors.initials: H
authors.lastname: VanBrocklin
authors.affiliation: Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA. Electronic address: cberkman@wsu.edu.
authors.forename: Clifford E
authors.initials: CE
authors.lastname: Berkman
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology; D011485:Protein Binding; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D014183:Transplantation, Heterologous
chemical_list: D000577:Amides; D000954:Antigens, Surface; D003287:Contrast Media; D010756:Phosphoric Acids; D019275:Radiopharmaceuticals; C011067:phosphoramidic acid; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: 4-Hydroxyproline; Inhibitor; Phosphoramidate; Prostate cancer; Prostate-specific membrane antigen