Structure-Activity Relationship of F-18-Labeled Phosphoramidate Peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-Targeted Inhibitor Analogues for PET Imaging of Prostate Cancer

0469119 - BTÚ 2017 RIV US eng J - Journal Article
Dannoon, S. - Ganguly, T. - Cahaya, H. - Geruntho, J. J. - Galliher, M. S. - Beyer, S. K. - Choy, C.J. - Hopkins, M.R. - Regan, M. - Blecha, J.E. - Škultétyová, Ĺubica - Drake, Ch.R. - Jivan, S. - Bařinka, Cyril - Jones, E. F. - Berkman, C.E. - VanBrocklin, H.F.
Structure-Activity Relationship of F-18-Labeled Phosphoramidate Peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-Targeted Inhibitor Analogues for PET Imaging of Prostate Cancer.
Journal of Medicinal Chemistry. Roč. 59, č. 12 (2016), s. 5684-5694. ISSN 0022-2623. E-ISSN 1520-4804
R&D Projects: GA ČR GAP301/12/1513; GA MŠMT(CZ) ED1.1.00/02.0109
Institutional support: RVO:86652036
Keywords : GLUTAMATE CARBOXYPEPTIDASE-II * REACTION-MECHANISM * FOLATE-HYDROLASE
Subject RIV: FD - Oncology ; Hematology
Impact factor: 6.259, year: 2016

A series of phosphoramidate-based prostate specific membrane antigen (PSMA) inhibitors of increasing lipophilicity were synthesized (4, 5, and 6), and their fluorine-18 analogs were evaluated for use as positron emission tomography (PET) imaging agents for prostate cancer. To gain insight into their modes of binding, they were also cocrystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50 values ranging from 0.4 to 1.3 nM. In vitro assays showed binding and rapid internalization (80-95%, 2 h) of the radiolabeled ligands in PSMA(+) cells. In vivo distribution demonstrated significant uptake in CWR22Rv1 (PSMA(+)) tumor, with tumor to blood ratios of 25.6:1, 63.6:1, and 69.6:1 for [F-18]4, [F-18]. 5, and [18F]6, respectively, at 2 h postinjection. Installation of aminohexanoic acid (AH) linkers in the phosphoramidate scaffold improved their PSMA binding and inhibition and was critical for achieving suitable in vivo imaging properties, positioning [F-18]5 and [F-18]6 as favorable candidates for future prostate cancer imaging clinical trials.
Permanent Link: http://hdl.handle.net/11104/0267007