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@ARTICLE{Eder:168092,
      author       = {A.-C. Eder$^*$ and M. Schaefer$^*$ and J. Schmidt$^*$ and
                      U. Bauder-Wuest and M. Roscher$^*$ and K. Leotta$^*$ and U.
                      Haberkorn and K. Kopka$^*$ and M. Eder$^*$},
      title        = {{R}ational {L}inker {D}esign to {A}ccelerate {E}xcretion
                      and {R}educe {B}ackground {U}ptake of {P}eptidomimetic
                      {PSMA}-{T}argeting {H}ybrid {M}olecules.},
      journal      = {Journal of nuclear medicine},
      volume       = {62},
      number       = {10},
      issn         = {2159-662X},
      address      = {New York, NY},
      publisher    = {Soc.},
      reportid     = {DKFZ-2021-00680},
      pages        = {1461-1467},
      year         = {2021},
      note         = {2021 Oct;62(10):1461-1467},
      abstract     = {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 $\%ID/g$ to 3.47±1.39 $\%ID/g$ (1 h p.i.). The
                      specific tumor uptake of this compound (7.59±0.95 $\%ID/g,$
                      1 h p.i.) was detected to be significantly higher as
                      compared to the parental tracer PSMA-11. These findings
                      confirmed by PET and fluorescence imaging are accompanied by
                      an enhanced pharmacokinetic profile with accelerated
                      background clearance at early time points post injection.
                      Conclusion: The novel generation of PSMA-targeting hybrid
                      molecules reveal fast elimination, reduced background organ
                      enrichment and high PSMA-specific tumor uptake meeting the
                      key demands for potent tracers in Nuclear Medicine and
                      fluorescence-guided surgery. The approach's efficacy of
                      improving the pharmacokinetic profile highlights the
                      strengths of rational linker design as a powerful tool in
                      strategic hybrid molecule development.},
      keywords     = {Optical (Other) / PSMA (Other) / Peptides (Other) /
                      Radiotracer Tissue Kinetics (Other) / guided-surgery (Other)
                      / hybrid molecules (Other) / pharmacokinetic profile (Other)
                      / prostate cancer (Other)},
      cin          = {FR01 / E060 / E030 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)FR01-20160331 / I:(DE-He78)E060-20160331 /
                      I:(DE-He78)E030-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {315 - Bildgebung und Radioonkologie (POF4-315)},
      pid          = {G:(DE-HGF)POF4-315},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33741642},
      doi          = {10.2967/jnumed.120.248443},
      url          = {https://inrepo02.dkfz.de/record/168092},
}