BACKGROUND: The enzyme-biomarker prostate-specific membrane antigen (PSMA) is an active target for imaging and therapeutic applications for prostate cancer.
The internalization of PSMA has been shown to vary with inhibitors' mode of binding: irreversible, slowly reversible, and reversible.
METHODS: In the present study, PSMA-targeted clickable derivatives of an irreversible phosphoramidate inhibitor DBCO-PEG4 -CTT-54 (IC50 = 1.0 nM) and a slowly reversible phosphate inhibitor, DBCO-PEG4 -CTT-54.2 (IC50 = 6.6 nM) were clicked to 99m Tc(CO)3 -DPA-azide to assemble a PSMA-targeted SPECT agent. The selectivity, percent uptake, and internalization of these PSMA-targeted SPECT agents were evaluated in PSMA-positive and PSMA-negative cells.
RESULTS: In vitro studies demonstrated that PSMA-targeted SPECT agents exhibited selective cellular uptake in the PSMA-positive LNCaP cells compared to PSMA-negative PC3 cells. More importantly, it was found that 99m Tc(CO)3 -DPA-DBCO-PEG4 -CTT-54 based on an irreversible PSMA inhibitor core, exhibited greater uptake and internalization than 99m Tc(CO)3 -DPA-DBCO-PEG4 -CTT-54.2 constructed from a slowly reversible PSMA inhibitor core.
CONCLUSIONS: We have demonstrated that a PSMA-targeted SPECT agent can be assembled efficiently using copper-less click chemistry. In addition, we demonstrated that mode of binding has an effect on internalization and percent uptake of PSMA-targeted SPECT agents; with the irreversible targeting agent demonstrating superior uptake and internalization in PSMA+ cells. The approach demonstrated in this work now supports a modular approach for the assembly of PSMA-targeted imaging and therapeutic agents.
Written by:
Nedrow-Byers JR, Moore AL, Ganguly T, Hopkins MR, Fulton MD, Benny PD, Berkman CE. Are you the author?
Department of Chemistry, Washington State University, Pullman, Washington.
Reference: Prostate. 2012 Aug 21. Epub ahead of print.
doi: 10.1002/pros.22575
PubMed Abstract
PMID: 22911263
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