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Pracoviště: Cancer Targeted Technology USA

1 záznamů v Medvik Filtry

Článek

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

Ganguly, Tanushree
Autor Ganguly, Tanushree Department of Chemistry, Washington State University, USA
Dannoon, Shorouk
Autor Dannoon, Shorouk Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA
Hopkins, Mark R
Autor Hopkins, Mark R Department of Chemistry, Washington State University, USA
Murphy, Stephanie
Autor Murphy, Stephanie Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA
Cahaya, Hendry
Autor Cahaya, Hendry Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA
Blecha, Joseph E
Autor Blecha, Joseph E Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA
Jivan, Salma
Autor Jivan, Salma Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA
Drake, Christopher R
Autor Drake, Christopher R Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA
Barinka, Cyril
Autor Barinka, Cyril Institute of Biotechnology, CR, Prague
Jones, Ella F
Autor Jones, Ella F Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA

Nuclear medicine and biology. 2015 ; 42 (10) : 780-7. [pub] 20150609

Nucl Med Biol
ISSN 1872-9614
Medvik
Zdroj

INTRODUCTION: 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. ADVANCES IN KNOWLEDGE: 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.

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