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

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 4h 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 4h. In vivo tumor uptake of 2.33% ID/g and tumor-to-blood ratio of 265:1 was observed at 4h.

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 [(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.

Nucl Med Biol. 2015 Jun 9. pii: S0969-8051(15)00095-5. doi: 10.1016/j.nucmedbio.2015.06.003. [Epub ahead of print]

Ganguly T1, Dannoon S2, Hopkins MR1, Murphy S2, Cahaya H2, Blecha JE2, Jivan S2, Drake CR2, Barinka C3, Jones EF2, VanBrocklin HF2, Berkman CE4.

1 Department of Chemistry, Washington State University, USA.
2 Department of Radiology and Biomedical Imaging, University of CA, San Francisco, USA.
3 Institute of Biotechnology, CR, Prague.
4 Department of Chemistry, Washington State University, USA; Cancer Targeted Technology, USA.