title: Assessment of an 18F-labeled phosphoramidate peptidomimetic as a new prostate-specific membrane antigen-targeted imaging agent for prostate cancer.
abstract: Prostate-specific membrane antigen (PSMA) is a transmembrane protein commonly found on the surface of late-stage and metastatic prostate cancer and a well-known imaging biomarker for staging and monitoring therapy. Although (111)In-labeled capropmab pendetide is the only approved agent available for PSMA imaging, its clinical use is limited because of its slow distribution and clearance that leads to challenging image interpretation. A small-molecule approach using radiolabeled urea-based PSMA inhibitors as imaging agents has shown promise for prostate cancer imaging. The motivation of this work is to explore phosphoramidates as a new class of potent PSMA inhibitors to develop more effective prostate cancer imaging agents with improved specificity and clearance properties.
  
  
  METHODS
  N-succinimidyl-4-(18)F-fluorobenzoate ((18)F-SFB) was conjugated to S-2-((2-(S-4-amino-4-carboxybutanamido)-S-2-carboxyethoxy)hydroxyphosphorylamino)-pentanedioic acid (Phosphoramidate (1)), yielding S-2-((2-(S-4-(4-(18)F-fluorobenzamido)-4-carboxybutanamido)-S-2-carboxyethoxy)hydroxyphosphorylamino)-pentanedioic acid (3). In vivo studies were conducted in mice bearing either LNCaP (PSMA-positive) or PC-3 (PSMA-negative) tumors. PET images were acquired at 1 and 2 h with or without a preinjection of a nonradioactive version of the fluorophosphoramidate. Tissue distribution studies were performed at the end of the 2 h imaging sessions.
  
  
  RESULTS
  Phosphoramidate (1) and its fluorobenzamido conjugate (2) were potent inhibitors of PSMA (inhibitory concentration of 50% [IC(50)], 14 and 0.68 nM, respectively). PSMA-mediated tumor accumulation was noted in the LNCaP versus the PC-3 tumor xenografts. The LNCaP tumor uptake was also blocked by the administration of nonradioactive (2) prior to imaging studies. With the exception of the kidneys, tumor-to-tissue and tumor-to-blood ratios were greater than 5:1 at 2 h. The strong kidney uptake may be due to the known PSMA expression in the mouse kidney, because significant reduction (>6-fold) in kidney activity was seen in mice injected with (2).
  
  
  CONCLUSIONS
  (18)F-labeled phosphoramidate (3) is a representative of a new class of PSMA targeting peptidomimetic molecules that shows great promise as imaging agents for detecting PSMA+ prostate tumors.
authors.affiliation: Department of Radiology and Biomedical Imaging, Center for Molecular and Functional Imaging, University of California, San Francisco, California 94107, USA.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Lapi
authors.forename: Hilla
authors.initials: H
authors.lastname: Wahnishe
authors.forename: David
authors.initials: D
authors.lastname: Pham
authors.forename: Lisa Y
authors.initials: LY
authors.lastname: Wu
authors.forename: Jessie R
authors.initials: JR
authors.lastname: Nedrow-Byers
authors.forename: Tiancheng
authors.initials: T
authors.lastname: Liu
authors.forename: Kaveh
authors.initials: K
authors.lastname: Vejdani
authors.forename: Henry F
authors.initials: HF
authors.lastname: VanBrocklin
authors.forename: Clifford E
authors.initials: CE
authors.lastname: Berkman
authors.forename: Ella F
authors.initials: EF
authors.lastname: Jones
mesh_terms: D000577:Amides / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D043425:Glutamate Carboxypeptidase II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D010455:Peptides / Q000737:chemistry*; D010756:Phosphoric Acids / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D014018:Tissue Distribution
chemical_list: D000577:Amides; D000954:Antigens, Surface; D005462:Fluorine Radioisotopes; D010455:Peptides; D010756:Phosphoric Acids; C011067:phosphoramidic acid; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II