Gear Up for a pH Shift: A Responsive Iron(II) 2‑Amino-6-picolyl-Appended Macrocyclic paraCEST Agent That Protonates at a Pendent Group

Two
high-spin Fe­(II) and Co­(II) complexes of 1,4,7,10-tetraazacyclododecane
(CYCLEN) appended with four 2-amino-6-picolyl groups, denoted as [Fe­(TAPC)]2+ and [Co­(TAPC)]2+, are reported. These complexes
demonstrate C2-symmetrical geometry from
coordination of two pendents, and they are present in a single diastereomeric
form in aqueous solution as shown by 1H NMR spectroscopy
and by a single-crystal X-ray structure for the Co­(II) complex. A
highly shifted but low-intensity CEST (chemical exchange saturation
transfer) signal from NH groups is observed at −118 ppm for
[Co­(TAPC)]2+ at pH 6.0 and 37 °C. A higher intensity
CEST peak is observed for [Fe­(TAPC)]2+, which demonstrates
a pH-dependent frequency shift from −72 to −79 ppm at
pH 7.7 to 4.8, respectively, at 37 °C. This shift in the CEST
peak correlates with the protonation of the unbound 2-amino-6-picolyl
pendents, as suggested by UV–vis and 1H NMR spectroscopy
studies at different pH values. Phantom imaging demonstrates the challenges
and feasibility of using the [Fe­(TAPC)]2+ agent on a low-field
MRI scanner. The [Fe­(TAPC)]2+ complex is the first transition-metal-based
paraCEST agent that produces a pH-induced CEST frequency change toward
the development of probes for concentration-independent imaging of
pH.