TY  - JOUR
AU  - Vanasschen, Christian
AU  - Molnár, Enikő
AU  - Tircsó, Gyula
AU  - Kálmán, Ferenc K.
AU  - Tóth, Éva
AU  - Brandt, Marie
AU  - Coenen, Heinz H.
AU  - Neumaier, Bernd
TI  - Novel CDTA-based, Bifunctional Chelators for Stable and Inert Mn II Complexation: Synthesis and Physicochemical Characterization
JO  - Inorganic chemistry
VL  - 56
IS  - 14
SN  - 1520-510X
CY  - Washington, DC
PB  - American Chemical Society
M1  - FZJ-2017-05201
SP  - 7746 - 7760
PY  - 2017
AB  - 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).
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000405972200021
C6  - pmid:28650621
DO  - DOI:10.1021/acs.inorgchem.7b00460
UR  - https://juser.fz-juelich.de/record/836077
ER  -