Assessment of an 18F-labeled phosphoramidate peptidomimetic as a new prostate-specific membrane antigen-targeted imaging agent for prostate cancer

Suzanne E. Lapi, Hilla Wahnishe, David Pham, Lisa Y. Wu, Jessie R. Nedrow-Byers, Tiancheng Liu, Kaveh Vejdani, Henry F. VanBrocklin, Clifford E. Berkman, Ella F. Jones

Research output: Contribution to journalArticle

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 111In-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-4-18F- fluorobenzoate (18F-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-(4-18F-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% [IC50], 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 signifi-cant reduction (>6-fold) in kidney activity was seen in mice injected with (2). Conclusion: 18F-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.

Original languageEnglish (US)
Pages (from-to)2042-2048
Number of pages7
JournalJournal of Nuclear Medicine
Volume50
Issue number12
DOIs
StatePublished - Dec 1 2009
Externally publishedYes

Keywords

  • F
  • Molecular imaging
  • PET
  • PSMA
  • Phosphoramidate
  • Prostate cancer
  • Radiopharmaceuticals

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

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