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@INPROCEEDINGS{Hoffmann:1026490,
      author       = {Hoffmann, Chris and Strecker, Jonas and Mittelstedt, Rik
                      and Spahn, Ingo and Neumaier, Bernd},
      title        = {2,6-{B}is-({N}-hydroxylamino)-1,3,5-triazines as ligands
                      for 45{T}i-chelation},
      reportid     = {FZJ-2024-03434},
      year         = {2023},
      abstract     = {Objectives: 45Ti (T½ = 3.1 h) is a promising PET
                      radionuclide thatcan be produced by proton irradiation of
                      nat Sc targets. While fasthydrolysis of most Ti(IV)
                      complexes has hampered their application forthe preparation
                      of 45Ti-labeled PET tracers[1] , some recently
                      reportedbis(hydroxyamino)triazine (BHT) complexes[2,3] are
                      hydrolyticallystable for several hours. Therefore, in this
                      study differently substitutedBHT ligands including a bridged
                      one were prepared and evaluated withregard to their
                      potential to form stable complexes with 45Ti.Additionally, a
                      novel procedure for the separation of 45Ti from the45 Sc
                      target material by cation exchange chromatography was
                      devel-oped[4]. Finally, a conjugate of a BHT-ligand with a
                      prostate-specificmembrane antigen (PSMA)-binding moiety
                      potentially suitable for thepreparation of 45 Ti-labeled
                      probes for imaging of prostate carcinomawas
                      synthesized.Methods: BHT ligands were prepared by
                      substitution of chlorinesubstituents in cyanuric chloride
                      first with secondary amines (R 3-NH-C 2 H4C(O)R4 ) followed
                      by hydroxylamines (R1-NH-OH, R2 -NH-OH)(Fig. 1)[2].Two
                      PSMA-selective probes were synthesized starting from
                      methyl3{-[(4,6-bis(chloro)-1,3,5-triazin-2-yl](R3
                      )amino}propanoate by sub-stitution of the chlorine atoms
                      with benzyl protected hydroxylamines,NaOH hydrolysis of CO
                      2Me to CO 2 H, conversion of the carboxylic groupinto a
                      succinimidyl ester, its reaction with t-butyl-protected
                      Lys-C(O)-Glu and, finally, two step deprotection of the
                      resulting intermediatewith HCl and H2 .For preparation of
                      the non-radioactive BHT-type complexes, asolution of the
                      corresponding BHT ligand, DIPEA and TiCl4 inanhydrous THF
                      was stirred for 30 min at room temperature.Subsequent
                      evaporation of the solvent provided the complexes asred
                      powders.For radiochemical separation of 45Ti the scandium
                      target was firstdissolved in 10 m HCl. The 45Ti-containing
                      solution was loaded onto aZR hydroxamate resin column
                      (Triskem, France). The column waswashed with 10 m HCl and
                      water to remove Sc and 45 Ti was eluted with 0.1 m oxalic
                      acid in phosphate buffer (pH = 8). Separation took
                      30minutes. For radiometal complex formation, the respective
                      ligand wasadded to the 45Ti-solution and the mixture was
                      stirred at roomtemperature for 45 min. Stability tests were
                      performed by incubationin phosphate-buffered saline (PBS, pH
                      = 7.4) at 36 °C followed by radio-TLC analysis.Results: The
                      separation and preparation protocols developed in thiswork
                      enabled the synthesis of 45Ti-labeled BHT complexes
                      inradiochemical conversions of $55\%$ - $90\%,$ as
                      determined by HPLC andradio-TLC analysis of the reaction
                      mixtures. The radiolabeled com-plexes including
                      PSMA-targeting conjugate showed a high stability inPBS (t
                      1/2 > 250 h). Conclusions: Easily accessible BHT ligands,
                      which form hydro-lytically stable Ti(IV) complexes, are
                      valuable tools for the develop-ment of 45Ti-labeled
                      PET-probes.References[1] Chaple F., et al. Appl. Radiat.
                      2020, 166, 109398.[2] Ekeltchik I. et al. Dalton Trans.
                      2006, 10, 1285–1293.[3] Peri D., et al. Dalton Trans.
                      2006, 34, 4169–4172.[4] Radchenko V. et al. J. Chromatogr.
                      A. 2016, 1477, 39–46},
      month         = {May},
      date          = {2023-05-22},
      organization  = {25th International Symposium on
                       Radiopharmaceutical Sciences, Honolulu,
                       USA (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/1026490},
}