%0 Journal Article
%A Eder, Ann-Christin
%A Schaefer, Martin
%A Schmidt, Jana
%A Bauder-Wuest, Ulrike
%A Roscher, Mareike
%A Leotta, Karin
%A Haberkorn, Uwe
%A Kopka, Klaus
%A Eder, Matthias
%T Rational Linker Design to Accelerate Excretion and Reduce Background Uptake of Peptidomimetic PSMA-Targeting Hybrid Molecules.
%J Journal of nuclear medicine
%V 62
%N 10
%@ 2159-662X
%C New York, NY
%I Soc.
%M DKFZ-2021-00680
%P 1461-1467
%D 2021
%Z 2021 Oct;62(10):1461-1467
%X The evolution of peptidomimetic hybrid molecules for preoperative imaging and guided surgery targeting the prostate-specific membrane antigen (PSMA) significantly progressed over the past years and some approaches are currently evaluated for further clinical translation. However, accumulation in non-malignant tissue such as kidney, bladder, spleen or liver might limit tumor-to-background contrast for precise lesion delineation particularly in a surgical setting. To overcome these limitations a rational linker design aims at the development of a second generation of PSMA-11 based hybrid molecules with enhanced pharmacokinetic profile and improved imaging contrasts. Methods: A selection of rational designed linkers was introduced to the PSMA-targeting hybrid molecule Glu-urea-Lys-HBED-CC-IRDye800CW resulting in a second generation peptidomimetic hybrid molecule library. The biological properties were investigated in cell-based assays. In a preclinical proof-of-concept study with the radionuclide 68Ga, the impact of the modifications was evaluated by determination of specific tumor uptake, pharmacokinetics and fluorescence-imaging in tumor-bearing mice. Results: The modified hybrid molecules carrying various selected linkers revealed high PSMA-specific binding affinity and effective internalization. The highest tumor-to-background contrast of all modifications investigated was identified for the introduction of a histidine (H) and glutamic acid (E) containing linker ((HE)3-linker) between PSMA-binding motif and chelator. In comparison to the parental core structure, uptake in non-malignant tissue was significantly reduced to a minimum exemplified by an 11-fold reduced spleen uptake from 38.12±14.62 
%K Optical (Other)
%K PSMA (Other)
%K Peptides (Other)
%K Radiotracer Tissue Kinetics (Other)
%K guided-surgery (Other)
%K hybrid molecules (Other)
%K pharmacokinetic profile (Other)
%K prostate cancer (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:33741642
%R 10.2967/jnumed.120.248443
%U https://inrepo02.dkfz.de/record/168092