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

Martin Schäfer1, Ulrike Bauder-Wüst1, Karin Leotta2, Frederic Zoller2, Walter Mier2, Uwe Haberkorn2, Michael Eisenhut1 and Matthias Eder1*

Author Affiliations

1 Radiopharmaceutical Chemistry, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

2 Department of Nuclear Medicine, University of Heidelberg, Im Neuenheimer Feld 400, Heidelberg, 69120, Germany

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EJNMMI Research 2012, 2:23  doi:10.1186/2191-219X-2-23

Published: 6 June 2012



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.


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.


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).


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.

Dimerization; 68Ga-PET imaging; PSMA; HBED-CC; Prostate cancer