Structure-Activity Relationship of 18F-labeled phosphoramidate peptidomimetic Prostate-Specific Membrane Antigen (PSMA)-targeted inhibitor analogues for PET imaging of prostate cancer

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 co-crystallized with the extracellular domain of PSMA. All analogs exhibited irreversible binding to PSMA with IC50's ranging from 0.4-1.3nM. In vitro whole cell assays showed binding and rapid internalization (80-95%, 2h) 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, 63.6 and 69.6 for [18F]4, [18F]5 and [18F]6, respectively, at 2h 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 [18F]5 and [18F]6 as favorable candidates for future prostate cancer imaging clinical trials.

Journal of medicinal chemistry. 2016 May 26 [Epub ahead of print]

Shorouk Dannoon, Tanushree Ganguly, Hendry Cahaya, Jonathan J Geruntho, Matthew S Galliher, Sophia K Beyer, Cindy Jan Choy, Mark R Hopkins, Melanie Regan, Joseph E Blecha, Lubica Skultetyova, Christopher R Drake, Salma Jivan, Cyril Barinka, Ella F Jones, Clifford E Berkman, Henry F VanBrocklin