The CEST (Chemical Exchange Saturation Transfer) MRI experiment is based on alterations in image contrast produced by transfer of selectively saturated spins from a chemical pool of contrast agent (CA) to a pool of bulk water.  The magnetization of the exchangeable protons (H2O, -NH, -OH) of CA is modulated by a presaturation pulse, and the water signal decreases upon exchange of the partially saturated protons.Fe(II) and Co(II) transition metal (TM) ions form paramagnetic complexes with TACN (1,4,7-triazacyclononane) or CYCLEN (1,4,7,10-tetraazacyclododecane) macrocycles with pendent heterocyclic donor groups that are suitable for CEST contrast.  TACN-based ligands containing 6-methyl-2-picolyl/5-amino-6-methyl-2-picolyl produce paramagnetic six-coordinate complexes with Fe(II) and Co(II).  These complexes are stabilized in a single diastereomeric form and have hyperfine shifted proton resonances (-20 to +200 ppm) with narrow line widths (60-800 Hz) in water.  CYCLEN derivatives with four 6-methyl-2-picolyl/6-amino-2-picolyl arms also stabilize paramagnetic states of Fe(II) and Co(II) in aqueous solution.  The hyperfine shifted proton resonances in these complexes span from -130 to +330 ppm.  1,7-Disubstituted CYCLEN with 6-methyl-2-picolyl pendants demonstrates similar hyperfine shifted proton resonances, suggesting a six-coordinate geometry of CYCLEN-based complexes.  Structurally similar CYCLEN-based complexes containing amino-picolyl pendants produced a paramagnetic CEST (paraCEST) effect with large chemical shift.Other heterocyclic donor groups including 1H-benzimidazol-2-ylmethyl and 1H-pyrazol-3-ylmethyl with TACN/CYCLEN macrocycles have been studied.  Reported Fe(II) and Co(II) CA are kinetically inert over a wide range of pH 5.0-8.5, as well as in the presence of physiologically relevant cations and anions.  A great variety of heterocyclic donors could be used to tune redox potential of Fe(II) and Co(II) complexes to physiological range (-100 to -300 mV) for redox-responsive MRI imaging.  The large shift of paraCEST peaks is promising in overcoming background from magnetization transfer (MT) effects in tissues.

Macrocyclic ligands with heterocyclic pendent groups for Fe(II) and Co(II) paraCEST MRI contrast agents

247th National Meeting (2014)

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