Comparison of Lanthanide Macrocyclic Complexes as ²³Na NMR Sensors

Nuclear magnetic resonance (NMR) agents, composed of paramagnetic lanthanide ions (Ln³⁺) complexed with negatively charged cyclic chelating agents (Che⁽) forming polyanionic lanthanide complexes (LnChe), perturb sodium-23 (²³Na) signals, a phenomenon which depends sodium ions (Na⁺) exchanging with LnChe. We analyzed ²³Na shiftability and broadening due to hyperfine and bulk magnetic susceptibility (BMS) effects that arise from LnChe designs using selective Ln³⁺ ions (i.e., thulium, Tm³⁺; gadolinium, Gd³⁺; and europium, Eu³⁺) and macrocyclics derived from 1,4,7,10-tetraazacyclododecane (cyclen) [i.e., with phosphonate (DOTP^8-) and carboxylate (DOTMA^4-) arms] and 1,4,7-triazacyclononane (TACN) [i.e., with phosphonate (NOTP^6-) arms]. All LnChe complexes showed downfield shifts, but Gd³⁺ and Tm³⁺ agents, respectively, were dominated by BMS and hyperfine effects, in good agreement with theory. While ²³Na shiftability and broadening were minimally affected by pH and competing cations (K⁺, Ca²⁺, and Mg²⁺) within physiological ranges, the ²³Na shiftability and broadening were most sensitive to LnChe concentration in relation to the interstitial Na⁺ level in vivo. Greatest ²³Na shiftability and broadening were obtained with Tm³⁺ and Gd³⁺ agents, respectively. While BMS contribution to shiftability was most impacted by the number of unpaired electrons on Ln³⁺, negative charge on LnChe regulated Na⁺ exchange for line broadening. In brain tumor models, TmDOTP^5- with ²³Na-NMR has been used previously to separate Na⁺ in intracellular, blood, and interstitial pools, while evidence here shows that GdDOTP^5- can distinguish Na⁺ within intracellular and extracellular (i.e., blood and interstitial) pools. Given the biological importance of Na⁺ in vivo, future macrocyclic designs of LnChe should be sought for ²³Na-NMR biomedical applications.