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@ARTICLE{Vanasschen:836077,
      author       = {Vanasschen, Christian and Molnár, Enikő and Tircsó,
                      Gyula and Kálmán, Ferenc K. and Tóth, Éva and Brandt,
                      Marie and Coenen, Heinz H. and Neumaier, Bernd},
      title        = {{N}ovel {CDTA}-based, {B}ifunctional {C}helators for
                      {S}table and {I}nert {M}n {II} {C}omplexation: {S}ynthesis
                      and {P}hysicochemical {C}haracterization},
      journal      = {Inorganic chemistry},
      volume       = {56},
      number       = {14},
      issn         = {1520-510X},
      address      = {Washington, DC},
      publisher    = {American Chemical Society},
      reportid     = {FZJ-2017-05201},
      pages        = {7746 - 7760},
      year         = {2017},
      abstract     = {In the search for MnIIMR and PET/MR imaging agents with
                      optimal balance between thermodynamic stability, kinetic
                      inertness, and relaxivity, two novel bifunctional MnII
                      chelators (BFMnCs) based on CDTA
                      (trans-1,2-diaminocyclohexane-N,N,N′,N′-tetraacetic
                      acid) weresynthesized. A six-step synthesis, involving the
                      buildup of a functionalized trans -1,2-diaminocyclohexane
                      core, provided CuAAC-reactive 6a and 6b bearing an alkyne or
                      azide substituent on the cyclohexane ring, respectively
                      (CuAAC = CuI-catalyzed azide−alkyne 1,3-dipolar
                      cyclo-addition). Thermodynamic, kinetic, and relaxometric
                      studies were performed with 4-HET-CDTA (8a)as a model
                      chelator, synthesized in two steps from6a. The protonation
                      constants revealed that8a is slightly less basic than CDTA
                      and forms a Mn II complex of marginally lower thermodynamic
                      stability (log KMnL= 13.80 vs 14.32, respectively), while
                      the conditional stability constant is almost identical for
                      both chelates (pMn = 8.62 vs 8.68, respectively). Kinetic
                      assessment of the CuII-mediated transmetalation of
                      [Mn(4-HET-CDTA)]2−showed that proton-assisted complex
                      dissociation is slightly slower than for [Mn(CDTA)]2−(k1=
                      297 vs 400 M−1s−1, respectively). portantly, the
                      dissociation half-life near physiologicalitions (pH 7.4,
                      25°C) underlined that $[Mn(4-HET-CDTA)]2−is∼35\%$ more
                      inert (t1/2= 16.2 vs 12.1 h, respectively).Thosefindings may
                      be accounted for by a combination of reduced basicity and
                      increased rigidity of the ligand. Analysis of the17O NMR
                      and1H NMRD data attributed the high relaxivity of
                      [Mn(4-HET-CDTA)]2−(r1= 4.56 mM−1s−1vs 3.65
                      mM−1s−1for [Mn(CDTA)]2−; 20 MHz, 25°C) to slower
                      rotational dynamics (τR298= 105 ps). Additionally, the fast
                      water exchange of thecomplex correlates well with the value
                      reported for [Mn(CDTA)]2−(kex298= 17.6×107vs
                      14.0×107s−1, respectively). Giventhe exquisite compromise
                      between thermodynamic stability, kinetic inertness, and
                      relaxivity achieved by [Mn(4-HET-CDTA)]2−,appropriately
                      designed CuAAC-conjugates of6a/6bare promising precursors
                      for the preparation of targeted, bioresponsive, orhigh
                      relaxivity manganese-based PET/MR tracers (52g/55MnII) and
                      MR contrast agents (MnII).},
      cin          = {INM-5},
      ddc          = {540},
      cid          = {I:(DE-Juel1)INM-5-20090406},
      pnm          = {573 - Neuroimaging (POF3-573)},
      pid          = {G:(DE-HGF)POF3-573},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000405972200021},
      pubmed       = {pmid:28650621},
      doi          = {10.1021/acs.inorgchem.7b00460},
      url          = {https://juser.fz-juelich.de/record/836077},
}