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@ARTICLE{Hajduov:304984,
      author       = {K. Hajduová and K. D. Bendová and M. Petřík and M.
                      Benesova-Schäfer$^*$ and M. Schäfer$^*$ and M. Hajdúch
                      and Z. Nový},
      title        = {{P}aving the way for future {PSMA} inhibitors: insights
                      from comparative preclinical evaluations of structure
                      modifications.},
      journal      = {EJNMMI radiopharmacy and chemistry},
      volume       = {10},
      number       = {1},
      issn         = {2365-421X},
      address      = {[Cham, Switzerland]},
      publisher    = {Springer International Publishing},
      reportid     = {DKFZ-2025-01975},
      pages        = {63},
      year         = {2025},
      abstract     = {Prostate-specific membrane antigen (PSMA) is an established
                      target for the imaging and treatment of prostate cancer.
                      This study focused on the preclinical evaluation of three
                      novel PSMA inhibitors-P15, P16, and P19-which were
                      structurally modified compared to the clinically used
                      PSMA-617. Two main strategies were pursued: a chemical
                      approach following the so-called reversed synthetic
                      strategy, and the replacement of the naphthyl-based linker
                      moiety with an analogous diphenyl-based moiety. The aim was
                      to assess the impact of these modifications on
                      physicochemical properties, in vitro behaviour, and in vivo
                      pharmacokinetics following radiolabelling with
                      ⁶⁸Ga.Radiolabelling of all three novel compounds with
                      ⁶⁸Ga resulted in high radiochemical purity above $98\%$
                      under physiological pH conditions and above $97\%$ during
                      stability testing in human plasma. All compounds exhibited
                      hydrophilic characteristics based on partition coefficient
                      measurements. Notable differences were observed in plasma
                      protein binding, with P15 and P16 showing significantly
                      lower binding compared to PSMA-617 and P19. In vitro assays
                      using LNCaP prostate cancer cells demonstrated similar
                      cellular uptake and internalization across all tested
                      compounds. In vivo evaluation using Positron Emission
                      Tomography/Computed Tomography (PET/CT) imaging in LNCaP
                      tumour-bearing mice confirmed the tumour-targeting ability
                      of all three inhibitors. These findings were further
                      supported by biodistribution studies, which highlighted
                      efficient and specific accumulation in tumour tissue. Among
                      the tested compounds, P19 demonstrated the most promising
                      overall profile in terms of stability, binding
                      characteristics, and tumour uptake.The stereochemical
                      modifications in the linker region significantly influenced
                      the in vitro and in vivo behaviour of the PSMA inhibitors.
                      Despite similar cellular uptake, differences in plasma
                      protein binding and pharmacokinetics were evident. Among the
                      three novel compounds, P19 emerged as a particularly
                      promising candidate for further investigation, also
                      indicating that the diphenyl moiety might serve as a
                      favourable linker building block in analogy to the naphthyl
                      moiety. Our observations suggest potential not only for
                      diagnostic imaging with ⁶⁸Ga, but also for therapeutic
                      applications using 177Lu, which offers a longer half-life
                      suitable for delayed imaging and treatment intervals in
                      prostate cancer management.},
      keywords     = {PSMA (Other) / Preclicnical PET/CT (Other) / Prostate
                      cancer (Other) / Radiopharmaceuticals (Other) / Theranostics
                      (Other)},
      cin          = {E270 / W630},
      ddc          = {610},
      cid          = {I:(DE-He78)E270-20160331 / I:(DE-He78)W630-20160331},
      pnm          = {315 - Bildgebung und Radioonkologie (POF4-315)},
      pid          = {G:(DE-HGF)POF4-315},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41003962},
      pmc          = {pmc:PMC12474757},
      doi          = {10.1186/s41181-025-00389-w},
      url          = {https://inrepo02.dkfz.de/record/304984},
}