Paramagnetic transition metal complexes that significantly shift proton resonances of ligands are utilized as molecular imaging probes. ParaSHIFT (paramagnetic chemical shift imaging) and paraCEST (paramagnetic Chemical Exchange Saturation Transfer) MRI contrast agents will be presented. Fe(II) and Co(II) complexes of TACN (1,4,7-triazacyclononane) with three 6-methyl-2-picolyl pendents ([M(MPT)]2+, M2+= Fe2+, Co2+) are structurally similar, stabilized in a single diastereomeric form, and have hyperfine (60-800 Hz linewidths) shifted proton resonances (–20 to +200 ppm) in water. The structures of Fe(II) and Co(II) complexes based on CYCLEN (1,4,7,10-tetraazacyclododecane) with four 6-methyl-2-picolyl pendents are six-coordinate in aqueous solution, as well as in the crystalline state with only two trans-pendents coordinated to the metal center (Fig. 1A). Two methyl groups of the C2-symmetrical [Co(TMPC)]2+ complex are shifted at -125 ppm from water and demonstrate the greatest temperature dependence with a temperature coefficient of 0.52 ppm/oC. Another CYCLEN-based Co(II) complex, [Co(BMPC)]2+, containing two 6-methyl-2-picolyl trans-pendents is six-coordinate and has less shifted proton resonances compared to [Co(TMPC)]2+ (Fig. 1B). The temperature-dependent hyperfine-shifted 1H-NMR resonances make these complexes promising for in vivo paraSHIFT temperature sensing. CYCLEN-based complexes of Fe(II) containing 2-amino-6-picolyl pendents demonstrate highly shifted NH proton resonances suitable for paraCEST MRI. The metal ions are stabilized in +2 oxidation state and complexes are kinetically inert over a wide range of pH values (5.0-8.5), as well as in the presence of biologically relevant cations and anions.

Transition metal complexes as paraSHIFT and paraCEST MRI contrast agents

249th National Meeting (2015)

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