The impact of rigidity and water exchange on the relaxivity of a dendritic MRI contrast agent.

Variable-temperature, multiple magnetic field (17)O NMR, EPR and variable-temperature (1)H nuclear magnetic relaxation dispersion (NMRD) measurement techniques have been applied to Gadomer 17, a new dendritic contrast agent for magnetic resonance imaging. The macromolecule bears 24 Gd(dota)-monoamide chelates (dota=N,N',N",N"'-tetracarboxymethyl-1,4,7,10-tetraazacyclododecane) attached to a lysine-based dendrimer. (17)O NMR and (1)H NMRD data were analysed simultaneously by incorporating the Lipari-Szabó approach for the description of rotational dynamics. The water exchange rate k(298)(ex)was found to be (1.0 +/- 0.1) x 10(6) s(-1), a value similar to those measured for other Gd(dota)-monoamide complexes, and the activation parameters DeltaH++ =24.7 +/- 1.3 kJ mol(-1) and DeltaS++ = -47.4 +/- 0.2 JK(-1) mol(-1). The internal flexibility of the macromolecule is characterised by the Lipari-Szabó order parameter S(2)=0.5 and a local rotational correlation time tau(298)(l)= 760 ps, whereas the global rotational correlation time of the dendrimer is much longer, tau(298)(g)=3050 ps. The analysis of proton relaxivities reveals that, beside slow water exchange, internal flexibility is an important limiting factor for imaging magnetic fields. Electronic relaxation, though faster than in similar, but monomeric, Gd(III) chelates, does not limit proton relaxivity of this contrast agent (r(1)=16.5mM(-1)s(-1) at 298 K and 20 MHz). This analysis provides direct clues for the design of high-efficiency contrast agents.