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EJNMMI Research
Published in: EJNMMI Research 1/2012

Open Access 01-12-2012 | Original research

A dimerized urea-based inhibitor of the prostate-specific membrane antigen for 68Ga-PET imaging of prostate cancer

Authors: Martin Schäfer, Ulrike Bauder-Wüst, Karin Leotta, Frederic Zoller, Walter Mier, Uwe Haberkorn, Michael Eisenhut, Matthias Eder

Published in: EJNMMI Research | Issue 1/2012

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Abstract

Background

Alternative positron-emission tomography (PET) probes like labeled inhibitors of the prostate-specific membrane antigen (PSMA) are of emerging clinical impact as they show the ability to image small lesions of recurrent prostate cancer. Here, the dimerization of the pharmacophore Glu‐ureido‐Lys via the 68Ga chelator N,N′-bis[2-hydroxy-5-(carboxyethyl)benzyl]ethylenediamine-N,N′-diacetic acid (HBED-CC) was investigated to further improve the binding characteristics and pharmacokinetics.

Methods

The peptidomimetic structures were synthesized by solid-phase chemistry, and the resulting products were coupled with the respective 2,3,5,6-tetrafluorophenol esters of HBED-CC to form the monomeric reference and the dimeric Glu‐ureido‐Lys derivative. The binding properties were analyzed in competitive binding, internalization, and cell surface retention experiments. PET images and biodistribution data were obtained 1 h after injection in BALB/c nu/nu mice bearing LNCaP tumor xenografts.

Results

Cell binding data revealed significant better binding properties of the dimer (IC50 = 3.9 ± 1.8 nM; IC50 (monomer) = 12.1 ± 2.1 nM). The inhibition potency investigated by the enzyme-based NAALADase assay confirmed these results. Specific internalization in LNCaP cells was demonstrated for both, the monomer and dimer. As shown by efflux measurements, the dimeric compound was more effectively retained on the cell surface, resulting in advanced in vivo properties (T/BMonomer = 9.2; T/BDimer = 26.5).

Conclusions

The dimeric [68Ga]7 is a promising imaging agent for PSMA-expressing tumors as it shows higher tumor uptake while observing more favorable background clearance. As compared to the respective monomer, the higher affinity and prolonged tumor retention additionally represent promising features and warrant further evaluation regarding 68Ga-PET imaging of PSMA expression.
Appendix
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Metadata
Title
A dimerized urea-based inhibitor of the prostate-specific membrane antigen for 68Ga-PET imaging of prostate cancer
Authors
Martin Schäfer
Ulrike Bauder-Wüst
Karin Leotta
Frederic Zoller
Walter Mier
Uwe Haberkorn
Michael Eisenhut
Matthias Eder
Publication date
01-12-2012
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2012
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/2191-219X-2-23

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