title: Structure-Activity Relationship of (18)F-Labeled Phosphoramidate Peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-Targeted Inhibitor Analogues for PET Imaging of Prostate Cancer.
abstract: A series of phosphoramidate-based prostate specific membrane antigen (PSMA) inhibitors of increasing lipophilicity were synthesized (4, 5, and 6), and their fluorine-18 analogs were evaluated for use as positron emission tomography (PET) imaging agents for prostate cancer. To gain insight into their modes of binding, they were also cocrystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50 values ranging from 0.4 to 1.3 nM. In vitro assays showed binding and rapid internalization (80-95%, 2 h) of the radiolabeled ligands in PSMA(+) cells. In vivo distribution demonstrated significant uptake in CWR22Rv1 (PSMA(+)) tumor, with tumor to blood ratios of 25.6:1, 63.6:1, and 69.6:1 for [(18)F]4, [(18)F]5, and [(18)F]6, respectively, at 2 h postinjection. Installation of aminohexanoic acid (AH) linkers in the phosphoramidate scaffold improved their PSMA binding and inhibition and was critical for achieving suitable in vivo imaging properties, positioning [(18)F]5 and [(18)F]6 as favorable candidates for future prostate cancer imaging clinical trials.
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California-San Francisco , 185 Berry Street, San Francisco, California 94107, United States.
authors.forename: Shorouk
authors.initials: S
authors.lastname: Dannoon
authors.affiliation: Department of Chemistry, Washington State University , Pullman, Washington 99164-4630, United States.
authors.forename: Tanushree
authors.initials: T
authors.lastname: Ganguly
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California-San Francisco , 185 Berry Street, San Francisco, California 94107, United States.
authors.forename: Hendry
authors.initials: H
authors.lastname: Cahaya
authors.affiliation: Department of Chemistry, Washington State University , Pullman, Washington 99164-4630, United States.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Geruntho
authors.affiliation: Department of Chemistry, Washington State University , Pullman, Washington 99164-4630, United States.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Galliher
authors.affiliation: Department of Chemistry, Washington State University , Pullman, Washington 99164-4630, United States.
authors.forename: Sophia K
authors.initials: SK
authors.lastname: Beyer
authors.affiliation: Department of Chemistry, Washington State University , Pullman, Washington 99164-4630, United States.
authors.forename: Cindy J
authors.initials: CJ
authors.lastname: Choy
authors.affiliation: Department of Chemistry, Washington State University , Pullman, Washington 99164-4630, United States.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hopkins
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California-San Francisco , 185 Berry Street, San Francisco, California 94107, United States.
authors.forename: Melanie
authors.initials: M
authors.lastname: Regan
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California-San Francisco , 185 Berry Street, San Francisco, California 94107, United States.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Blecha
authors.affiliation: Institute of Biotechnology , 252 50 Prague, Czech Republic.
authors.forename: Lubica
authors.initials: L
authors.lastname: Skultetyova
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California-San Francisco , 185 Berry Street, San Francisco, California 94107, United States.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Drake
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California-San Francisco , 185 Berry Street, San Francisco, California 94107, United States.
authors.forename: Salma
authors.initials: S
authors.lastname: Jivan
authors.affiliation: Institute of Biotechnology , 252 50 Prague, Czech Republic.
authors.forename: Cyril
authors.initials: C
authors.lastname: Barinka
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California-San Francisco , 185 Berry Street, San Francisco, California 94107, United States.
authors.forename: Ella F
authors.initials: EF
authors.lastname: Jones
authors.affiliation: Department of Chemistry, Washington State University , Pullman, Washington 99164-4630, United States.|Cancer Targeted Technology , Woodinville, Washington 98072, United States.
authors.forename: Clifford E
authors.initials: CE
authors.lastname: Berkman
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California-San Francisco , 185 Berry Street, San Francisco, California 94107, United States.
authors.forename: Henry F
authors.initials: HF
authors.lastname: VanBrocklin
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000954:Antigens, Surface; D004305:Dose-Response Relationship, Drug; D005462:Fluorine Radioisotopes; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000000981:diagnostic imaging; D057786:Peptidomimetics / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000577:Amides; D000954:Antigens, Surface; D005462:Fluorine Radioisotopes; D057786:Peptidomimetics; D010756:Phosphoric Acids; C011067:phosphoramidic acid; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II