A high-affinity [18F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer

Ganguly, Tanushree; Dannoon, Shorouk; Hopkins, Mark R.; Murphy, Stephanie; Cahaya, Hendry; Blecha, Joseph E.; Jivan, Salma; Drake, Christopher R.; Barinka, Cyril; Jones, Ella F.; VanBrocklin, Henry F.; Berkman, Clifford E.

doi:10.1016/j.nucmedbio.2015.06.003

Title: A high-affinity [¹⁸F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer

Journal Article · Tue Jun 09 00:00:00 EDT 2015 · Nuclear Medicine and Biology

DOI:https://doi.org/10.1016/j.nucmedbio.2015.06.003· OSTI ID:1214298

Ganguly, Tanushree ^[1]; Dannoon, Shorouk ^[2]; Hopkins, Mark R. ^[1]; Murphy, Stephanie ^[2]; Cahaya, Hendry ^[2]; Blecha, Joseph E. ^[2]; Jivan, Salma ^[2]; Drake, Christopher R. ^[2]; Barinka, Cyril ^[3]; Jones, Ella F. ^[2]; VanBrocklin, Henry F. ^[2]; Berkman, Clifford E. ^[4]

Washington State Univ., Pullman, WA (United States). Dept. of Chemistry
Univ. of California, San Francisco, CA (United States). Dept. of Radiology and Biomedical Imaging
Inst. of Biotechnology, Prague (Czech Republic)
Washington State Univ., Pullman, WA (United States). Dept. of Chemistry; Cancer Targeted Technology, Woodinville, WA (United States)

Here 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. 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. [¹⁸F]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. 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 [¹⁸F]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. In conclusion, 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 [¹⁸F]5 in PSMA(+) xenografts substantiates its potential use for PET imaging of PCa.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: W-31-109-Eng-38; R01 CA140617; W81XWH-11-1-0464; 301/12/1513; CZ.1.05/1.1.00/02.0109

OSTI ID:: 1214298

Alternate ID(s):: OSTI ID: 1252095

Journal Information:: Nuclear Medicine and Biology, Vol. 42, Issue 10; ISSN 0969-8051

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 42 works

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¹⁷⁷Lu-Labeled Phosphoramidate-Based PSMA Inhibitors: The Effect of an Albumin Binder on Biodistribution and Therapeutic Efficacy in Prostate Tumor-Bearing Mice Choy, Cindy J.; Ling, Xiaoxi; Geruntho, Jonathan J. Theranostics, Vol. 7, Issue 7 https://doi.org/10.7150/thno.18719	journal	January 2017

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Title: A high-affinity [18F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer

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Title: A high-affinity [¹⁸F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer