Iron(II) Complexes Containing Octadentate Tetraazamacrocycles as ParaCEST Magnetic Resonance Imaging Contrast Agents

Iron­(II) complexes of the macrocyclic ligands 1,4,7,10-tetrakis­(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (TCMC) and (1<i>S</i>,4<i>S</i>,7<i>S</i>,10<i>S</i>)-1,4,7,10-tetrakis­(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane (STHP) contain a highly stabilized Fe^II center in the high-spin state, which is encapsulated by an octadentate macrocycle. The complexes are resistant to acid, metal cations, phosphate, carbonate, and oxygen in aqueous solution. [Fe­(TCMC)]²⁺ contains exchangeable amide protons, and [Fe­(STHP)]²⁺ contains exchangeable protons attributed to alcohol OH donors, which give chemical exchange saturation transfer (CEST) peaks at physiological pH and 37 °C at 50 and 54 ppm from bulk water, respectively. The distinct pH dependence of the CEST peak of the two complexes over the range of pH 6–8 shows that these two groups may be useful in the development of ratiometric pH sensors based on iron­(II)

The NiCEST Approach: Nickel(II) ParaCEST MRI Contrast Agents

Paramagnetic Ni­(II) complexes are shown here to form paraCEST MRI contrast agents (paraCEST = paramagnetic chemical exchange saturation transfer; NiCEST = Ni­(II) based CEST agents). Three azamacrocycles with amide pendent groups bind Ni­(II) to form stable NiCEST contrast agents including 1,4,7-tris­(carbamoylmethyl)-1,4,7-triazacyclononane (<b>L1</b>), 1,4,8,11-tetrakis­(carbamoylmethyl)-1,4,8,11-tetraazacyclotetradecane (<b>L2</b>), and 7,13-bis­(carbamoylmethyl)-1,4,10-trioxa-7,13-diazacyclopentadecane (<b>L3</b>). [Ni­(<b>L3</b>)]²⁺, [Ni­(<b>L1</b>)]²⁺, and [Ni­(<b>L2</b>)]²⁺ have CEST peaks attributed to amide protons that are shifted 72, 76, and 76 ppm from the bulk water resonance, respectively. Both CEST MR images and CEST spectroscopy show that [Ni­(<b>L3</b>)]²⁺ has the largest CEST effect in 100 mM NaCl, 20 mM HEPES pH 7.4 at 37 °C. This larger CEST effect is attributed to the sharper proton resonances of the complex which arise from a rigid structure and low relaxivity