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(n+3)–) forming polyanionic lanthanide complexes (LnChen–), perturb sodium-23 (23Na) signals, a phenomenon which depends sodium ions (Na+) exchanging with LnChen–. We analyzed 23Na shiftability and broadening due to hyperfine and bulk magnetic susceptibility (BMS) effects that arise from LnChen– 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 (DOTP8–) and carboxylate (DOTMA4–) arms] and 1,4,7-triazacyclononane (TACN) [i.e., with phosphonate (NOTP6–) arms]. All LnChen– 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 LnChen– 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 LnChen– regulated Na+ exchange for line broadening. In brain tumor models, TmDOTP5– with 23Na-NMR has been used previously to separate Na+ in intracellular, blood, and interstitial pools, while evidence here shows that GdDOTP5– 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 LnChen– should be sought for 23Na-NMR biomedical applications.