Abstract
Understanding the relationship between chemical structure and the effectiveness of bioresponsive magnetic resonance imaging (MRI) contrast agents can offer help to identify key components required for the future development of such probes. Here, we report the development and characterisation of two novel monomeric bifunctional chelators, L1 and L2, whose paramagnetic metal complexes can serve as calcium-responsive contrast agents. Specifically, relaxometric titrations, luminescence lifetime measurements, high resolution NMR and diffusion experiments, as well as density functional theory (DFT) calculations were carried out to assess the behaviour of each system. Minor structural differences between the probes resulted from the extension of the linker between the macrocyclic lanthanide chelator and the acyclic Ca-binding moiety. Relaxometric titrations of both systems, GdL1 and GdL2, showed an increase in r1 and r2 relaxivity upon Ca2+ addition, with the derivative bearing the longer linker showing a greater overall change. The hydration states of the europium analogues were assessed revealing a higher initial hydration state for EuL2. Diffusion ordered NMR spectroscopy revealed negligible changes in the diffusive properties of both systems upon the addition of Ca2+, while NMR studies of the Y3+, Yb3+ and Eu3+ analogues provided further insights into the structural behaviour of the linker unit in both the unsaturated and Ca-saturated states. DFT calculations supported the different coordination modes of the studied paramagnetic complexes in the presence and absence of Ca2+. Overall, our findings demonstrate the impact of subtle changes to the structure of such probes, affecting a range of properties and their coordination behaviour.
Highlights
Magnetic resonance imaging (MRI) is an essential diagnostic imaging technique used widely in clinics to provide three dimensional soft tissue images at high spatial resolution
Many attempts to develop Ca-responsive smart contrast agents (SCAs) have been pursued over recent years resulting in the production of a variety of molecules ranging from smaller monomeric compounds to larger nanosized derivatives.[3,12,13]
Through the use of a variety of techniques such as 1D and 2D NMR, luminescence lifetime measurements, diffusion ordered NMR spectroscopy (DOSY), density functional theory (DFT) calculations and proton relaxometric titrations, we aimed to characterize the newly developed probes and gain an insight into how subtle structural differences impact on their relaxometric and coordination behaviour
Summary
Magnetic resonance imaging (MRI) is an essential diagnostic imaging technique used widely in clinics to provide three dimensional soft tissue images at high spatial resolution. Many attempts to develop Ca-responsive SCAs have been pursued over recent years resulting in the production of a variety of molecules ranging from smaller monomeric compounds to larger nanosized derivatives.[3,12,13] The desire to understand the relationship between SCA structure and relaxometric enhancement has brought about a series of studies investigating such effects, providing significant insights into the behaviour of these systems.[14,15] the interaction of the carboxylates from the Ca-binding chelate with the paramagnetic metal ion or the roles of the two stereoisomers, square antiprismatic (SAP) and twisted square antiprismatic (TSAP), of 1,4,7,10-tetraazacyclododecane-1,4,7-tris(methylenecarboxylic) acid (DO3A) macrocyclic chelators have revealed interesting coordination properties of these responsive systems. It was evaluated that the shorter ethyl linker is likely to be too close to the paramagnetic metal centre hindering the interaction of the carboxylate group with Gd3+
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