RESEARCH NOTE
Effect of Solvent on Gd(DOTA)– Complex Formation: A Preliminary Investigation
Ernest Guiller S. Pineda and Aaron Joseph L. Villaraza*
Institute of Chemistry, College of Science, University of the Philippines Diliman,
Quezon City, Metro Manila 1101 Philippines
*Corresponding author: This email address is being protected from spambots. You need JavaScript enabled to view it.
ABSTRACT
The thermodynamic stability and kinetic inertness of gadolinium-based MRI contrast agents remains an important research topic in the field of radiological contrast agent development. In this study, the kinetics and thermodynamics of Gd3+-complex formation with the macrocyclic ligand DOTA (i.e., 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) was investigated under aqueous (acetate buffer pH 5.8) and non-aqueous (MeOH) conditions. Using Job’s method of continuous variation, solutions were prepared of increasing mole fraction of Gd3+ relative to xylenol orange (XO, i.e., 3,3′-bis[N,N-bis(carboxymethyl)aminomethyl]-o-cresolsulfonephthalein) in MeOH, and their absorbances were measured at 582 nm.The kinetics of complex formation via ligand substitution of DOTA and DO3A (i.e., 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid) with Gd-XO under aqueous and non-aqueous conditions were determined using UV-Vis spectrophotometry. Furthermore, the thermodynamic parameters of DOTA complexation with Gd3+ for both solvent conditions were compared by measuring the heats of injection using isothermal titration calorimetry. Results of this study demonstrate that XO forms a well-defined 1:1 stoichiometry with Gd3+ regardless of solvent polarity. Meanwhile, the rate of ligand substitution between Gd-XO and the macrocyclic ligand is effectively minimized under non-aqueous conditions (kobs, buffer= 33.9 ± 1.0 x 10–3 s–1; kobs,MeOH = 5.62 ± 2.22 x 10–3 s–1). The binding reaction of Gd3+ with DOTA has comparable negative ΔG values in the two solvents (ΔGbuffer= ‒9.28 ± 0.57 kcal/mol; ΔGMeOH = ‒8.19 ± 0.14 kcal/mol), suggesting that the reaction is equally spontaneous under both conditions. However, computation of global thermodynamic properties demonstrate that the reaction is entropically-driven in acetate buffer in comparison with MeOH where the reaction is enthalpy-driven. Finally, the nature of solvent has an effect on the metal-to-ligand stoichiometry (N) of the resulting complex, which in acetate buffer (N = 1:1) is lower than that in MeOH (N = 1:2). These results are important in the context of optimizing reaction conditions in the preparation of related MRI contrast agents.
INTRODUCTION
The stability of Gd3+-complexes with macrocyclic ligands in the context of radiologic contrast agent (CA) development for clinical use remains a topic of interest, as in vivo decomplexation of Gd3+ is associated not only with the onset of Nephrogenic System Fibrosis (NSF) but also with Gd3+ accumulation in the brain of healthy patients (Garcia et al. 2017). . . . . read more
REFERENCES
BELLEZA OJV, NARAGA AMB, VILLARAZA AJL. 2018. Relative ligand exchange rates in Gd-based MRI contrast agent formation as probed by Gd-XO complex. J Chin Chem Soc 65: 561–566.
GARCIA J, LIU SZ, LOUIE AY. 2017. Biological effects of MRI contrast agents: Gadolinium retention, potential mechanisms and a role for phosphorus. Phil Trans R Soc A 375: 20170180.
JOB P. 1928. Formation and stability of inorganic complexes in solution. Ann Chim Appl 9: 113–203.
NATRAJAN LS, VILLARAZA AJL, KENWRIGHT AM, FAULKNER S. 2009. Controlled preparation of a heterometallic lanthanide complex containing different lanthanides in symmetrical binding pockets. Chem Commun 6020–22.
O’BRIEN LC, ROOT HB, WEI CC, JENSEN D, SHABESTARY N, DE MEO C, EDER DJ. 2015. M2+•EDTA binding affinities: A modern experiment in thermodynamics for the physical chemistry laboratory. J Chem Educ 92: 1547–51.
PÉREZ-MALO M, SZABÓ G, EPPARD E, VAGNER A, BRÜCHER E, TÓTH I, MAIOCCHI A, SUH EH, KOVÁCS Z, BARANYAI Z, RÓSCH F. 2018. Improved efficacy of synthesizing MIII-labeled DOTA complexes in binary mixtures of water and organic solvents: A combined radio- and physicochemical study. Inorg Chem 57: 6107–17.
ROCHESTER CH. 1972. The ionic products of water and methanol in methanol-water mixtures. J Chem Soc Dalton Trans 5–8.
ROUNAGHI GH, SOORGI MH, KAZEMI MS. 2010. Effect of non-aqueous solvents on stoichiometry and selectivity of complexes formed between 4′-nitrobenzo-15-crown-5 with Fe3+, Y3+, Cd2+, Sn4+, Ce3+ and Au3+ metal cations. Russ J Inorg Chem 55: 355–360.
SUAZO KFG, VILLARAZA AJL. 2015. Gd-XO: A colourimetric probe for the complexation of Gd3+ with DO3A-type ligands. Anal Methods 7: 8967–69.
