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

0450935 - BTÚ 2016 RIV US eng J - Journal Article
Ganguly, T. - Dannoon, S. - Hopkins, M.R. - Murphy, S. - Cahaya, H. - Blecha, J.E. - Jivan, S. - Drake, Ch.R. - Bařinka, Cyril - Jones, E.F. - VanBrocklin, H.F. - Berkman, C.E.
A high-affinity [(18) F]-labeled phosphoramidate peptidomimetic PSMA-targeted inhibitor for PET imaging of prostate cancer.
Nuclear Medicine and Biology. Roč. 42, č. 10 (2015), s. 780-787. ISSN 0969-8051. E-ISSN 1872-9614
R&D Projects: GA MŠMT(CZ) ED1.1.00/02.0109; GA ČR GAP301/12/1513
Keywords : Flourine-18 * PET * Phosphoramidate * PSMA
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 2.429, year: 2015

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. [F-18]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 [F-18]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 [F-18]5 in PSMA(+) xenografts substantiates its potential use for PET imaging of PCa.
Permanent Link: http://hdl.handle.net/11104/0252132