Trigger ready: A redox‐activated MRI contrast agent can cycle between paramagnetic CoII (MRI‐active) and diamagnetic CoIII (MRI‐silent). The paramagnetic CoII form produces a highly shifted CEST signal at 135 ppm (37 °C). The redox state of the Co complex is altered by O2 partial pressure and reductant concentration (thiols) on a time scale relevant to imaging. MT=magnetization transfer.

The first examples of Fe(II) PARACEST magnetic resonance contrast agents are reported (PARACEST = paramagnetic chemical exchange saturation transfer). The iron(II) complexes contain a macrocyclic ligand, either 1,4,7-tris(carbamoylmethyl)-1,4,7-triazacyclononane (L1) or 1,4,7-tris[(5-amino-6-methyl-2-pyridyl)methyl]-1,4,7-triazacyclononane (L2). The macrocycles bind Fe(II) in aqueous solution with formation constants of log K = 15.6 and 19.2, respectively and maintain the Fe(II) state in the presence of air. These complexes each contain six exchangeable protons for CEST which are amide protons in [Fe(L1)]2+ or amino protons in [Fe(L2)]2+. The CEST peak for the [Fe(L1)]2+ amide protons is at 69 ppm downfield of the bulk water resonance whereas the CEST peak for the [Fe(L2)]2+ amine protons is at 6 ppm downfield of bulk water. CEST imaging using a MRI scanner shows that the CEST effect can be observed in solutions containing low millimolar concentrations of complex at neutral pH, 100 mM NaCl, 20 mM buffer at 22 °C or 37 °C.

Transition metal ion-based paraCEST agents (TM-CEST) are a promising new class of compounds for MRI contrast. Members in this class of compounds include paramagnetic complexes of FeII, CoII and NiII. The development of the coordination chemistry for these paraCEST agents is presented with an emphasis on the choice of azamacrocycle backbone and pendent groups with the goals of controlling oxidation state, spin state and stability of the complexes. CEST spectra and images are compared for different macrocyclic complexes containing amide or heterocyclic pendent groups. The potential of paraCEST agents that function as pH and redox-activated MRI probes is discussed.

Paramagnetic Fe(II) and Co(II) complexes are utilized as the first transition metal examples of 1H NMR shift agents (paraSHIFT) for thermometry applications using Magnetic Resonance Spectroscopy (MRS). The coordinating ligands consist of TACN (1,4,7-triazacyclononane) and CYCLEN (1,4,7,10-tetraazacyclododecane) azamacrocycles appended with 6-methyl-2-picolyl groups, denoted as MPT and TMPC, respectively. 1H NMR spectra of the MPT- and TMPC-based Fe(II) and Co(II) complexes demonstrate narrow and highly shifted resonances that are dispersed as broadly as 440 ppm. The six-coordinate complex cations, [M(MPT)]2+ and [M(TMPC)]2+, vary from distorted octahedral to distorted trigonal prismatic geometries, respectively, and also demonstrate that 6-methyl-2-picolyl pendents control the rigidity of these complexes. Analyses of the 1H NMR chemical shifts, integrated intensities, line widths, the distances obtained from X-ray diffraction measurements and longitudinal relaxation time (T1) values allow for the partial assignment of proton resonances of the [M(MPT)]2+ complexes. Nine and six equivalent methyl protons of [M(MPT)]2+ and [M(TMPC)]2+, respectively, produce three-fold higher 1H NMR intensities compared to other paramagnetically shifted proton resonances. Among all four complexes, the methyl proton resonances of [Fe(TMPC)]2+ and [Co(TMPC)]2+ at −49.3 ppm and −113.7 ppm (37 °C) demonstrate the greatest temperature dependent coefficients (CT) of 0.23 ppm/°C and 0.52 ppm/°C, respectively. The methyl groups of these two complexes both produce normalized values of |CT|/FWHM = 0.30 °C−1, where FWHM is full width at half maximum (Hz) of proton resonances. The T1 values of the highly shifted methyl protons are in the range of 0.37–2.4 ms, allowing rapid acquisition of spectroscopic data. These complexes are kinetically inert over a wide range of pH values (5.6–8.6), as well as in the presence of serum albumin and biologically relevant cations and anions. The combination of large hyperfine shifts, large temperature sensitivity, increased signal-to-noise ratio and short T1 values suggests that these complexes, in particular the TMPC-based complexes, show promise as paraSHIFT agents for thermometry.

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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 pH 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 towards the development of probes for concentration independent imaging of pH.