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PSMA‐targeted SPECT agents: Mode of binding effect on in vitro performance
Author(s) -
NedrowByers Jessie R.,
Moore Adam L.,
Ganguly Tanushree,
Hopkins Mark R.,
Fulton Melody D.,
Benny Paul D.,
Berkman Clifford E.
Publication year - 2013
Publication title -
the prostate
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.295
H-Index - 123
eISSN - 1097-0045
pISSN - 0270-4137
DOI - 10.1002/pros.22575
Subject(s) - internalization , lncap , glutamate carboxypeptidase ii , chemistry , cancer research , in vitro , click chemistry , prostate cancer , biophysics , biochemistry , cell , medicine , combinatorial chemistry , cancer , biology
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‐PEG 4 ‐CTT‐54 (IC 50 = 1.0 nM) and a slowly reversible phosphate inhibitor, DBCO‐PEG 4 ‐CTT‐54.2 (IC 50 = 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‐PEG 4 ‐CTT‐54 based on an irreversible PSMA inhibitor core, exhibited greater uptake and internalization than 99m Tc(CO) 3 ‐DPA‐DBCO‐PEG 4 ‐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. Prostate 73: 355–362, 2013. © 2012 Wiley Periodicals, Inc.