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

Abstract

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.

• Authors: Tanushree Ganguly, Shorouk Dannoon, Mark R Hopkins, Stephanie Murphy, Hendry Cahaya, Joseph E Blecha, Salma Jivan, Christopher R Drake, Cyril Barinka, Ella F Jones, Henry F VanBrocklin, Clifford E Berkman
• Journal: Nuclear medicine and biology (Nucl Med Biol) Vol. 42 Issue 10 Pg. 780-7 (Oct 2015) ISSN: 1872-9614 [Electronic] United States
• PMID: 26169882 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Amides
• Antigens, Surface
• Fluorine Radioisotopes
• Peptidomimetics
• Phosphoric Acids
• Protease Inhibitors
• phosphoramidic acid
• FOLH1 protein, human
• Glutamate Carboxypeptidase II

Topics

• Amides (chemistry)
• Animals
• Antigens, Surface (chemistry)
• Biological Transport
• Cell Line, Tumor
• Drug Stability
• Fluorine Radioisotopes
• Glutamate Carboxypeptidase II (antagonists & inhibitors, chemistry)
• Humans
• Inhibitory Concentration 50
• Isotope Labeling
• Male
• Mice
• Models, Molecular
• Peptidomimetics (chemistry, metabolism, pharmacokinetics, pharmacology)
• Phosphoric Acids (chemistry)
• Positron-Emission Tomography (methods)
• Prostatic Neoplasms (diagnostic imaging, pathology)
• Protease Inhibitors (chemistry, metabolism, pharmacokinetics, pharmacology)
• Protein Conformation
• Tissue Distribution