TY  - JOUR
AU  - Eder, Ann-Christin
AU  - Schaefer, Martin
AU  - Schmidt, Jana
AU  - Bauder-Wuest, Ulrike
AU  - Roscher, Mareike
AU  - Leotta, Karin
AU  - Haberkorn, Uwe
AU  - Kopka, Klaus
AU  - Eder, Matthias
TI  - Rational Linker Design to Accelerate Excretion and Reduce Background Uptake of Peptidomimetic PSMA-Targeting Hybrid Molecules.
JO  - Journal of nuclear medicine
VL  - 62
IS  - 10
SN  - 2159-662X
CY  - New York, NY
PB  - Soc.
M1  - DKFZ-2021-00680
SP  - 1461-1467
PY  - 2021
N1  - 2021 Oct;62(10):1461-1467
AB  - 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 
KW  - Optical (Other)
KW  - PSMA (Other)
KW  - Peptides (Other)
KW  - Radiotracer Tissue Kinetics (Other)
KW  - guided-surgery (Other)
KW  - hybrid molecules (Other)
KW  - pharmacokinetic profile (Other)
KW  - prostate cancer (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:33741642
DO  - DOI:10.2967/jnumed.120.248443
UR  - https://inrepo02.dkfz.de/record/168092
ER  -