Engineering lanthanide complexes with controlled water exchange rates for magnetic resonance imaging
The control of the rate of water exchange in lanthanide complexes is critical to their future development as contrast agents in magnetic resonance imaging. In traditional T/sub 1/ shortening agents an optimal water residence lifetime (/spl tau//sub M/) of around 25 ns is required if the highest relaxivities are to be achieved. In contrast the newer PARACEST agents require that water exchange is much slower with /spl tau//sub M/ on the order of microseconds. It is now possible to rationally design complexes that exhibit water exchange rates that are ideal for their intended use. The selection of appropriate ligating groups allow a broad control mechanism. Anionic ligating groups such as carboxylates favour faster exchange whereas neutral ligands such as amides favour slower exchange. By altering the steric hindrance around the water coordination site water exchange rates can be fine tuned. The steric hindrance can be altered by controlling the coordination environment of the lanthanide ion and optimal water exchanges rates so achieved.
Quantification of water exchange kinetics for targeted PARACEST perfluorocarbon nanoparticles
PARACEST (PARAmagnetic Chemical Exchange Saturation Transfer) agents offer the ability to generate “contrast on demand”, negating the need to image before contrast agent injection. Perfluorocarbon (PFC) nanoparticles can deliver very large payloads of PARACEST agents, lowering the effective detection limit for molecular imaging of sparse biomarkers. Also, the PFC core provides a quantitative 19F signal for measuring particle binding with high signal intensity and no background signal. 19F quantization coupled with mathematical modeling of the PARACEST signal showed that incorporating PARACEST chelates onto the nanoparticle surface reduces the bound water lifetime and diminishes the available contrast to noise ratio compared to the parent small molecule PARACEST chelate. PARACEST nanoparticles were targeted to fibrin, an early biomarker for atherosclerotic plaque rupture, and bound to the surface of in vitro clots, yielding a detection limit of 2.30 nM at 11.7T. When the particles bind to a target surface, the image contrast is higher than predicted from phantom experiments, perhaps due to improved water exchange kinetics. We demonstrated that PARACEST PFC nanoparticles can provide two unique signatures, 19F and PARACEST, for quantitative targeted molecular imaging of fibrin. Copyright © 2011 John Wiley & Sons, Ltd.
Nuclear magnetic resonance and potentiometric studies of the protonation scheme of a triaza triacetic macrocycle and its complexes with lanthanum and lutetium
The protonation constants of the macrocyclic ligand 1,4,7-triazacyclononane-N,N’,N”-triacetic acid (NOTA) have been measured by potentiometry, and the protonation sequence of the various amino and carboxylate groups of NOTA has been studied in DzO as a function of pD from the chemical shifts of the nonlabile protons. Shielding constants for protonation of the amino groups were determined in a NMR study of the triaza macrocyclic amine, its trimethylated analogue, and NOTA and compared with values reported for linear polyamino polycarboxylates and cyclic tetraaza tetracarboxylate ligands. The results indicate that two nitrogens of NOTA are protonated at higher pH than the carboxylate groups. The last nitrogen is protonated only at very low pH. The sequence of protonation of NOTA supports the formation of hydrogen bonds between two protonated nitrogens and the adjacent two nonprotonated carboxylates. The ‘H and I3C spectra of the La(N0TA) and Lu(N0TA) species were studied as a function of pH and temperature. The aqueous complexes show spectra characteristic of flexible triaza macrocycles, displaying fast interconversion between the two staggered 6 and X conformations of the ethylenediamine rings even at room temperature. Above pH 9.5, the La(N0TA) and Lu(N0TA) hydroxo complexes start to form and their spectra show evidence of greater rigidity as at room temperature the 6 /X ethylenediamine ring conformational interconversions in the Lu(N0TA) hydroxo complex are slow on the NMR time scale.