Targeting PSMA with a Cu-64 Labeled Phosphoramidate Inhibitor for PET/CT Imaging of Variant PSMA-Expressing Xenografts in Mouse Models of Prostate Cancer

Jessie R. Nedrow, Joseph D. Latoche, Kathryn E. Day, Jalpa Modi, Tanushree Ganguly, Dexing Zeng, Brenda F. Kurland, Clifford E. Berkman, Carolyn J. Anderson

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Purpose: Prostate-specific membrane antigen (PSMA) is highly up-regulated in prostate tumor cells, providing an ideal target for imaging applications of prostate cancer. CTT-1297 (IC50 = 27 nM) is an irreversible phosphoramidate inhibitor of PSMA that has been conjugated to the CB-TE1K1P chelator for incorporation of Cu-64. The resulting positron emission tomography (PET) agent, [64Cu]ABN-1, was evaluated for selective uptake both in vitro and in vivo in PSMA-positive cells of varying expression levels. The focus of this study was to assess the ability of [64Cu]ABN-1 to detect and distinguish varying levels of PSMA in a panel of prostate tumor-bearing mouse models. Procedures: CTT-1297 was conjugated to the CB-TE1K1P chelator using click chemistry and radiolabeled with Cu-64. Internalization and binding affinity of [64Cu]ABN-1 was evaluated in the following cell lines having varying levels of PSMA expression: LNCaP late-passage > LNCaP early passage ≈ C4-2B > CWR22rv1 and PSMA-negative PC-3 cells. PET/X-ray computed tomography imaging was performed in NCr nude mice with subcutaneous tumors of the variant PSMA-expressing cell lines. Results: [64Cu]ABN-1 demonstrated excellent uptake in PSMA-positive cells in vitro, with ∼80 % internalization at 4 h for each PSMA-positive cell line with uptake (fmol/mg) correlating to PSMA expression levels. The imaging data indicated significant tumor uptake in all models. The biodistribution for late-passage LNCaP (highest PSMA expression) demonstrated the highest specific uptake of [64Cu]ABN-1 with tumor-to-muscle and tumor-to-blood ratios of 30 ± 11 and 21 ± 7, respectively, at 24 h post-injection. [64Cu]ABN-1 cleared through all tissues except for PSMA-positive kidneys. Conclusion: [64Cu]ABN-1 demonstrated selective uptake in PSMA-positive cells and tumors, which correlated to the level of PSMA expression. The data reported herein suggest that [64Cu]ABN-1 will selectively target and image variant PSMA expression and in the future will serve as a non-invasive method to follow the progression of prostate cancer in men.

Original languageEnglish (US)
Pages (from-to)402-410
Number of pages9
JournalMolecular Imaging and Biology
Volume18
Issue number3
DOIs
Publication statusPublished - Jan 1 2016
Externally publishedYes

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Keywords

  • Copper-64
  • Irreversible inhibitor
  • PET
  • Phosphoramidate
  • PSMA

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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