Solution chemistry and structure of CoII, Fe II and NiII amide-appended macrocyclic paracest agents and LnIII coordination to DNA analogs
Olatunde, Abiola O.
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Transition metal paramagnetic chemical exchange saturation transfer (paraCEST) agents were developed and optimized as responsive pH-and temperature-dependent probes for magnetic resonance imaging (MRI). This dissertation is focused on the solution chemistry and solid state structures of the Co(II), Fe(II), and Ni(II) complexes of amide- appended triaza-, tetraaza-, and mixed aza-oxo macrocyclic paraCEST agents. Crystallographic data showed that nitrogen and oxygen donor atoms of the hexa-, hepta- or octa-dentate amide-append macrocyclic ligands coordinate to the metal ions and generated six-, seven- or eight- coordinate complexes. The proton NMR spectra of the complexes showed highly dispersed proton resonances that were either relatively sharp or broad depending on the metal center. Complexes were further characterized by monitoring their dissociation under biologically relevant conditions including solutions containing phosphate and carbonate or Zn(II) . Also, the dissociation of the complexes under acidic conditions (pD 2-4) was monitored over a 12 hour period. Solutions of the paraCEST agents in 20 mM HEPES (pH 7.4) and 100 mM NaCl showed highly shifted (40-112 ppm) and intense CEST peaks (9-40%) at 37 oC on a 11.7 T NMR spectrometer. Temperature-dependent CEST experiments uncovered complexes with improved sensitivity and temperature coefficient values in the range -0.56 to -0.12 ppm/oC. Complexes were studied in rabbit serum, 4% agarose gel (w/w), or egg white to simulate possible in vivo interactions with biomacromolecules. CEST spectra with corresponding rate constants for proton exchange are reported under these conditions. CEST phantoms of the complexes on a 4.7 T MRI scanner at 37 oC are compared. These in vitro CEST NMR and MRI experiments indicate that the complexes show promise for use as probes for mapping in vivo pH changes or paraCEST thermometry imaging. The third chapter of this dissertation is focused on the tetradentate PNA-HOPO and simple bidentate 1-Hydroxy-2-(1H)-pyridinone-2-carboxylic acid propylamide (Pr-1,2-HOPO) interaction with the nine coordinate Eu(III) ion. Peptide nucleic acids (PNA) that are modified to contain bidentate ligands for lanthanide ion binding are under development as target specific MRI contrast agents. The substitution of a nucleobase pair with 1,2-hydroxypyridinones (1,2-HOPO) introduced a binding site for lanthanide(III) ions in the HOPO-modified PNA duplex (PNA-HOPO). Non-modified PNA does not bind strongly to lanthanide(III) ions. Ln(III)-1,2-HOPO complexes are useful for sensitizing Ln(III) ion luminescence for biological imaging and Ln(III) based MRI. Direct excitation Ln(III) luminescence, sensitized luminescence, optical thermal melting experiments, and UV-vis titrations confirmed the coordination of the Eu(III) to PNA-HOPO. Studies of the PNA-HOPO duplex were compared to non-modified PNA duplex and Pr-1,2-HOPO to determine the binding mode.