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@INPROCEEDINGS{Humpert:1026498,
      author       = {Humpert, Swen and Elsner, Anna-Lena and Zlatopolskiy, Boris
                      and Neumaier, Bernd},
      title        = {{T}owards covalent fibroplast activation protein ({FAP})
                      inhibitors for delivery of therapeutic radionuclides into
                      {FAP}-positive tumors},
      reportid     = {FZJ-2024-03442},
      year         = {2023},
      abstract     = {Objectives: Fibroblast activation protein (FAP) inhibitors
                      based on a(4-quinolinoyl)-glycyl-2-cyanopyrrolidine scaffold
                      are promising leadstructures for the development of
                      FAP-selective positron emissiontomography (PET) tracers.1
                      However, due to their fastwashout, they arenot suitable for
                      delivery of therapeutic radionuclides into FAP-positivetumor
                      lesions. The aim of the present work was to overcome
                      thislimitation by replacement of the cyano group with a
                      sulfonyl fluoridebasedwarhead, which should enable
                      irreversible covalent binding ofthe inhibitor through an in
                      vivo click reaction with the active-siteserine residue.2
                      Radiofluorination of the warhead was used as astrategy to
                      verify formation of covalent binding by detection of
                      thedeliberated [18F]fluoride.Methods: First the FAP
                      inhibitor scaffold was prepared by a threestepconvergent
                      synthesis. The sulfonyl fluoridewarheadwas preparedby a five
                      step convergent synthesis starting from N-Cbz-L-prolinol.
                      Thismoiety was acylated with 4-quinoloyl-glycine
                      conventionally accessiblein three steps. Radiolabeling was
                      performed using a protocol forultrafast 18F/19F isotopic
                      exchange by “SuFEx click chemistry”.3 To thisend,
                      [18F]fluoride was loaded onto a QMA anion exchange
                      cartridgeand eluted with a solution of BnEt3NCl in MeOH.
                      Followingevaporation of the solvent and addition of the
                      radiolabeling precursorin MeCN (1 mL), the reaction was
                      allowed to proceed at 0°C for 5 minunder argon without
                      stirring. Isolation of the radiotracer for
                      subsequentstability tests in various media at different pH
                      values wasperformed by solid phase extraction (SPE) on a
                      C-18 cartridge.Results: The radiolabeling precursorwas
                      obtained in a total yield $of11\%$ over nine steps and
                      radiolabeled with radiochemical conversionsof 50 ± $11\%$
                      (n = 7), affording the desired radiofluorinated compound
                      inactivity yields of 27 ± $1.4\%$ (n = 4) after isolation
                      by SPE. Subsequentincubation studies demonstrated excellent
                      stability of the radiolabeledproduct in acidic media at pH
                      values between 4 and 5 for at least twohours, even after
                      heating at 100 °C for 5 min. However, the compoundexhibited
                      defluorination in H2O, phosphate-buffered saline (PBS)
                      atphysiological pH (7.4), and rapid defluorination in blood
                      serum, with ahalf-life of 117,124 and 5.7 min, respectively.
                      Due to lowstability of thetracer in PBS and blood serum,
                      further optimization of the structure iscurrently ongoing
                      before binding studies will be performed by in vivoPET
                      imaging.Conclusions: A modified FAP inhibitor derivative
                      with a sulfonylfluoride-based warhead was successfully
                      synthesized and radiofluorinated.However, in vivo covalent
                      binding of the warhead to theFAP enzyme could not be
                      examined due to insufficient stability inblood serum and at
                      physiological pH value.References1. Jansen K., Heirbaut L.,
                      Cheng J. D., Joossens J., Ryabtsova O., Cos P.,Maes L.,
                      Lambeir A-M., De Meester I., Augustyns K., Van derVeken P.,
                      ACS Med. Chem. Lett. 2013, 4, 491–496.2. Narayanan A.,
                      Jones L. H., Chem. Sci. 2015, 6, 2650–2659.3. Walter N.,
                      Bertram J., Drewes B., Bahutski V., Timmer M., SchützM. B.,
                      Krämer F., Neumaier F., Endepols H., Neumaier
                      B.,Zlatopolskiy B. D., Eur. J. Med. Chem. 2022, 237,
                      114383.},
      month         = {May},
      date          = {2023-05-22},
      organization  = {25th International Symposium on
                       Radiopharmaceutical Sciences, Honolulu
                       (USA), 22 May 2023 - 26 May 2023},
      subtyp        = {After Call},
      cin          = {INM-5},
      cid          = {I:(DE-Juel1)INM-5-20090406},
      pnm          = {5253 - Neuroimaging (POF4-525)},
      pid          = {G:(DE-HGF)POF4-5253},
      typ          = {PUB:(DE-HGF)6},
      url          = {https://juser.fz-juelich.de/record/1026498},
}