Ion-Pairing Interactions between Co(en)(3)(3+) and the (23)Na NMR Frequency Shift Reagent TmDOTP(5)(-)

Three new formulations of TmDOTP(5)(-) (DOTP(8)(-) = 1,4,7,10-tetraazacyclododecane-1,4,7,11-tetrakis(methylenephosphonate)) have been prepared in an effort to develop a low-osmolality form of the (23)Na frequency shift reagent (SR). Equally concentrated (0.32 M) solutions of (MegH)(4)HTmDOTP (Meg = N-methylglucamine or meglumine), Na(4)HTmDOTP, and [Co(en)(3)](4/3)HTmDOTP have solution osmolalities of 1245, 1040, and 707 mOsm/kg, respectively, comparable to the ionic and non-ionic gadolinium-based MRI contrast agent preparations in clinical use. An analysis of (23)Na and (59)Co frequency shifts induced by TmDOTP(5)(-) indicated that Co(en)(3)(3+) can form both 1:1 and 2:1 adducts with TmDOTP(5)(-) with (log) binding constants of 3.1 +/- 0.4 and 2.5 +/- 0.4, respectively. These values were comparable with those obtained by analysis of the (1)H frequency shifts observed for Co(en)(3)(3+) upon binding to HoDOTP(5)(-). The (1)H shifts of Co(en)(3)(3+) signals induced by YbDOTP(5)(-) at pH 7.4 were fitted best by a 1:1 binding model with a conditional binding constant of 3.1 +/- 0.2. The (59)Co and (1)H limiting frequency shifts of Co(en)(3)(3+) could be fitted with a dipolar shift model in which the Co atom of the Co(en)(3)(3+) cation is located 5.0 +/- 0.3 Å from the Ln atom of the LnDOTP(5)(-) chelate, and with an angle of 40 +/- 0.2 degrees between the Co-Ln vector and the 4-fold symmetry axis of the LnDOTP(5)(-) complex. Ion pairing of Co(en)(3)(3+) and TmDOTP(5)(-) was significant enough in both saline and human blood plasma to reduce the effectiveness of the (23)Na frequency SR. Comparisons between all formulations suggested that Na(4)HTmDOTP represents the best compromise of lower osmolality with minimal reduction of SR shift potency.