PSMA-targeted SPECT agents: mode of binding effect on in vitro performance

Jessie R Nedrow-Byers; Adam L Moore; Tanushree Ganguly; Mark R Hopkins; Melody D Fulton; Paul D Benny; Clifford E Berkman

doi:10.1002/pros.22575

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PSMA-targeted SPECT agents: mode of binding effect on in vitro performance

Journal article

Open access

Peer reviewed

PSMA-targeted SPECT agents: mode of binding effect on in vitro performance

Jessie R Nedrow-Byers, Adam L Moore, Tanushree Ganguly, Mark R Hopkins, Melody D Fulton, Paul D Benny and Clifford E Berkman

The Prostate, Vol.73(4), pp.355-362

03/2013

DOI: https://doi.org/10.1002/pros.22575

Handle:

https://hdl.handle.net/2376/105726

PMCID: PMC4414331

PMID: 22911263

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Abstract

Prostatic Neoplasms - metabolism

Prostatic Neoplasms - pathology

Humans

Tomography, Emission-Computed, Single-Photon

Male

Prostatic Neoplasms - diagnosis

Radioisotopes - metabolism

Glutamate Carboxypeptidase II - metabolism

Antigens, Surface - metabolism

Cell Line, Tumor

Drug Delivery Systems - methods

Cell Survival - physiology

Protein Binding - physiology

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. 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. 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. 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.

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Title: PSMA-targeted SPECT agents: mode of binding effect on in vitro performance
Creators: Jessie R Nedrow-Byers - Department of Chemistry, Washington State University, Pullman, Washington 99164-4630, USA
Adam L Moore
Tanushree Ganguly
Mark R Hopkins
Melody D Fulton
Paul D Benny
Clifford E Berkman
Publication Details: The Prostate, Vol.73(4), pp.355-362
Academic Unit: Chemistry, Department of
Publisher: United States
Grant note: R01CA140617 / NCI NIH HHS R01 CA140617 / NCI NIH HHS
Identifiers: 99900547059201842
Language: English
Resource Type: Journal article