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 (L1), 1,4,8,11- tetrakis(carbamoylmethyl)-1,4,8,11-tetraazacyclotetradecane (L2), and 7,13-bis(carbamoylmethyl)-1,4,10-trioxa-7,13-diazacyclopentadecane (L3). [Ni(L3)]²⁺, [Ni(L1)]²⁺, and [Ni(L2)]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(L3)]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.