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

Abstract

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 [18F]4, [18F] 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 [18F]5 and [18F]6 as favorable candidates for future prostate cancer imaging clinical trials.

Toward the Discovery and Development of PSMA Targeted Inhibitors for Nuclear Medicine Applications

“…An irreversible binding profile is desirable because it might induce a higher rate of internalization than weaker interaction and consequently, rapid in vivo tumor uptake after the administration and greater contrast with the background tissues [ 42 ]. Conversely, reversible binding may explain the tumor washout over several hours observed with urea-based inhibitors [ 43 ].…”

“…A series of FB ring-containing compounds derivative of CTT1057 were designed in order to further understand the SAR of phosphoramidates respect to the interactions within the ABS and to evaluate their corresponding in vivo pharmacokinetics and biodistribution [ 43 ].…”

Glu-Ureido–Based Inhibitors of Prostate-Specific Membrane Antigen: Lessons Learned During the Development of a Novel Class of Low-Molecular-Weight Theranostic Radiotracers

“…Additionally, it facilitates the engagement of these moieties with structurally defined pockets in the entrance funnel (e.g., the S1 accessory hydrophobic pocket or the arene-binding site), thus contributing to the increased affinity of such bivalent ligands for PSMA ( Fig. 6) and allowing for the structure-assisted design of the next generation of ligands (48,(51)(52)(53)(54)(55).…”

Radiolabelled Peptides for Positron Emission Tomography and Endoradiotherapy in Oncology

“…Contrary to other PSMA targeting compounds, which are urea-based, [ 18 F]F-CTT1057 is a phosphoramidate-based PSMA inhibitor. This compound resulted from a series of derivatives which differ in the linker between binding sequence and 4-[ 18 F]fluorobenzoyl group [171]. A preliminary study with patients showed a low radiation burden as well as similar distribution as found for urea-based analogues like [ 18 F]F-DCFPyL [166].…”