ParaCEST (paramagnetic Chemical Exchange Saturation Transfer) MRI contrast agents based on Iron(II) and Cobalt(II) complexes will be presented. In these complexes, the transition metal ions are coordinated to the N-donor atoms of macrocyclic ligands, such as TACN (1,4,7-triazacyclononane) or CYCLEN (1,4,7,10-tetraazacyclododecane), and to the N-donor atoms of the appendant heterocycles. These ligands stabilize the +2 oxidation state, as well as, the high-spin state of the metal ions, producing paramagnetic complexes. The heterocyclic pendents also contain exchangeable NH protons, which are functional for CEST MRI. Irradiation at the resonant frequency of the exchangeable NH proton partially saturates the spin state and, upon exchange with bulk water protons, gives a decrease in the water proton signal, which is observed in an MRI experiment. The [Co(TPT)]2+ complex of TACN macrocycle appendant with three 1H-pyrazol-3-yl-methyl groups produces a highly-shifted CEST signal at +135 ppm from bulk water at 37 oC. The [Co(TPT)]2+ CEST effect is highly pH-dependent, which is optimized at pH 6.9-7.0. This complex is redox-active under biological conditions with Eo(Co3+/Co2+) = -107±10 mV vs. NHE. The [Co(TPT)]2+ paraCEST MRI contrast is turn-on under reducing conditions (L-Cys, glutathione), while oxidation to [Co(TPT)]3+ with O2 results in paraCEST MRI contrast turn-off. These redox properties make [Co(TPT)]2+ promising for paraCEST imaging under hypoxic conditions. The [Fe(TAPC)]2+, a complex of the CYCLEN macrocycle appendant with four 2-amino-6-picolyl groups, produces a highly-shifted paraCEST signal at -72 ppm from bulk water (pH 7.2, 37 oC). The [Fe(TAPC)]2+ CEST effect is maximal at pH 5.9-6.0, which is promising for imaging of acidosis in tumors. Presented paraCEST agents are kinetically inert over a wide range of pH values, as well as in the presence of physiologically relevant cations and anions. The combination of highly-shifted CEST peaks, pH- and redox-responsiveness makes these paraCEST agents promising for in vivo imaging.

Iron(II) and cobalt (II) paraCEST MRI contrast agents responsive to pH and redox environment

249th National Meeting (2015)

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