[¹⁸F]Fluorobenzoyllysinepentanedioic Acid Carbamates: New Scaffolds for Positron Emission Tomography (PET) Imaging of Prostate-Specific Membrane Antigen (PSMA)

Abstract

Radiolabeled urea-based low-molecular weight inhibitors of the prostate-specific membrane antigen (PSMA) are under intense investigation as imaging and therapeutic agents for prostate and other cancers. In an effort to provide agents with less nontarget organ uptake than the ureas, we synthesized four 18F-labeled inhibitors of PSMA based on carbamate scaffolds. 4-Bromo-2-[18F]fluorobenzoyllysineoxypentanedioic acid (OPA) carbamate [18F]23 and 4-iodo-2-[18F]fluorobenzoyllysine OPA carbamate [18F]24 in particular exhibited high target-selective uptake in PSMA+ PC3 PIP tumor xenografts, with tumor-to-kidney ratios of >1 by 4 h postinjection, an important benchmark. Because of its high tumor uptake (90% injected dose per gram of tissue at 2 h postinjection) and high tumor-to-organ ratios, [18F] 23 is promising for clinical translation. Prolonged tumor-specific uptake demonstrated by [18F]24, which did not reach equilibrium during the 4 h study period, suggests carbamates as alternative scaffolds for mitigating dose to nontarget tissues.

Development of prostate specific membrane antigen targeted ultrasound microbubbles using bioorthogonal chemistry

“…This model was selected as it has been used to evaluate the ability of other molecular imaging probes [40] to differentiate between PSMA + and PSMA − tumors. In this study, MB Tz-TCO -ARP was injected and allowed to circulate for 4 min.…”

Mouse glutamate carboxypeptidase II (GCPII) has a similar enzyme activity and inhibition profile but a different tissue distribution to human GCPII

“…The assay was performed with the same tissue samples used in the western blot analysis. number of papers have been published describing novel GCPII inhibitors acting as neuroprotective drugs [28,44] and GCPII inhibitor-based tools for imaging and/or treating prostate cancer [19,20,[45][46][47]. Most of these compounds and methods were evaluated using mouse models.…”

Prostate-Specific Membrane Antigen Ligands for Imaging and Therapy

“…The first class of PSMA-targeting radiopharmaceuticals based on phosphorous esters failed in early clinical translation (57). Other promising lead structures, such as carbamates, are still in preclinical evaluation (58). The focus of this review is the clinically most advanced category, the urea-based PSMA ligands, which usually consist of 3 components: the binding motif (glutamate-urea-lysine [Glu-urea-Lys] is the most widely used scaffold), a linker, and a radiolabel-bearing moiety (chelator molecule for radiolabeling or a prosthetic group for fluorinated agents) (Fig.…”