title: A high-affinity [(18)F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer.
abstract: BACKGROUND
  In this study, a structurally modified phosphoramidate scaffold, with improved prostate-specific membrane antigen (PSMA) avidity, stability and in vivo characteristics, as a PET imaging agent for prostate cancer (PCa), was prepared and evaluated.
  
  
  METHODS
  p-Fluorobenzoyl-aminohexanoate and 2-(3-hydroxypropyl)glycine were introduced into the PSMA-targeting scaffold yielding phosphoramidate 5. X-ray crystallography was performed on the PSMA/5 complex. [(18)F]5 was synthesized, and cell uptake and internalization studies were conducted in PSMA(+) LNCaP and CWR22Rv1 cells and PSMA(-) PC-3 cells. In vivo PET imaging and biodistribution studies were performed at 1 and 4 h post injection in mice bearing CWR22Rv1 tumor, with or without blocking agent.
  
  
  RESULTS
  The crystallographic data showed interaction of the p-fluorobenzoyl group with an arene-binding cleft on the PSMA surface. In vitro studies revealed elevated uptake of [(18)F]5 in PSMA(+) cells (2.2% in CWR22Rv1 and 12.1% in LNCaP) compared to PSMA(-) cells (0.08%) at 4 h. In vivo tumor uptake of 2.33% ID/g and tumor-to-blood ratio of 265:1 was observed at 4 h.
  
  
  CONCLUSIONS
  We have successfully synthesized, radiolabeled and evaluated a new PSMA-targeted PET agent. The crystal structure of the PSMA/5 complex highlighted the interactions within the arene-binding cleft contributing to the overall complex stability. The high target uptake and rapid non-target clearance exhibited by [(18)F]5 in PSMA(+) xenografts substantiates its potential use for PET imaging of PCa.
  
  
  CONCLUSIONS
  The only FDA-approved imaging agent for PCa, Prostascint®, targets PSMA but suffers from inherent shortcomings. The data acquired in this manuscript confirmed that our new generation of [(18)F]-labeled PSMA inhibitor exhibited promising in vivo performance as a PET imaging agent for PCa and is well-positioned for subsequent clinical trials. Implications for Patient Care Our preliminary data demonstrate that this tracer possesses the required imaging characteristics to be sensitive and specific for PCa imaging in patients at all stages of the disease.
authors.affiliation: Department of Chemistry, Washington State University, USA.
authors.forename: Tanushree
authors.initials: T
authors.lastname: Ganguly
authors.affiliation: Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA.
authors.forename: Shorouk
authors.initials: S
authors.lastname: Dannoon
authors.affiliation: Department of Chemistry, Washington State University, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Hopkins
authors.affiliation: Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Murphy
authors.affiliation: Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA.
authors.forename: Hendry
authors.initials: H
authors.lastname: Cahaya
authors.affiliation: Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Blecha
authors.affiliation: Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA.
authors.forename: Salma
authors.initials: S
authors.lastname: Jivan
authors.affiliation: Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Drake
authors.affiliation: Institute of Biotechnology, CR, Prague.
authors.forename: Cyril
authors.initials: C
authors.lastname: Barinka
authors.affiliation: Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA.
authors.forename: Ella F
authors.initials: EF
authors.lastname: Jones
authors.affiliation: Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA.
authors.forename: Henry F
authors.initials: HF
authors.lastname: VanBrocklin
authors.affiliation: Department of Chemistry, Washington State University, USA; Cancer Targeted Technology, USA. Electronic address: cberkman@wsu.edu.
authors.forename: Clifford E
authors.initials: CE
authors.lastname: Berkman
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D000954:Antigens, Surface / Q000737:chemistry; D001692:Biological Transport; D045744:Cell Line, Tumor; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008958:Models, Molecular; D057786:Peptidomimetics / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D010756:Phosphoric Acids / Q000737:chemistry*; D049268:Positron-Emission Tomography / Q000379:methods*; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000473:pathology; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D011487:Protein Conformation; D014018:Tissue Distribution
chemical_list: D000577:Amides; D000954:Antigens, Surface; D005462:Fluorine Radioisotopes; D057786:Peptidomimetics; D010756:Phosphoric Acids; D011480:Protease Inhibitors; C011067:phosphoramidic acid; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II
keywords: Flourine-18; PET; PSMA; Phosphoramidate