Comparison of Lanthanide Macrocyclic Complexes as Na NMR Sensors.

Nuclear magnetic resonance (NMR) agents, composed of paramagnetic lanthanide ions (Ln) complexed with negatively charged cyclic chelating agents (Che) forming polyanionic lanthanide complexes (LnChe), perturb sodium-23 (Na) signals, a phenomenon which depends sodium ions (Na) exchanging with LnChe. We analyzed Na shiftability and broadening due to hyperfine and bulk magnetic susceptibility (BMS) effects that arise from LnChe designs using selective Ln ions (, thulium, Tm; gadolinium, Gd; and europium, Eu) and macrocyclics derived from 1,4,7,10-tetraazacyclododecane (cyclen) [, with phosphonate (DOTP) and carboxylate (DOTMA) arms] and 1,4,7-triazacyclononane (TACN) [, with phosphonate (NOTP) arms]. All LnChe complexes showed downfield shifts, but Gd and Tm agents, respectively, were dominated by BMS and hyperfine effects, in good agreement with theory. While Na shiftability and broadening were minimally affected by pH and competing cations (K, Ca, and Mg) within physiological ranges, the Na shiftability and broadening were most sensitive to LnChe concentration in relation to the interstitial Na level . Greatest Na shiftability and broadening were obtained with Tm and Gd agents, respectively. While BMS contribution to shiftability was most impacted by the number of unpaired electrons on Ln, negative charge on LnChe regulated Na exchange for line broadening. In brain tumor models, TmDOTP with Na-NMR has been used previously to separate Na in intracellular, blood, and interstitial pools, while evidence here shows that GdDOTP can distinguish Na within intracellular and extracellular (, blood and interstitial) pools. Given the biological importance of Na , future macrocyclic designs of LnChe should be sought for Na-NMR biomedical applications.