| Abstract
| - We report a mechanistic investigation of an isomeric series of β-galactosidase-activated magnetic resonance contrast agents. For the β-series of agents, a bidentate anion occupies two available coordination sites of Gd(III) until cleavage of the sugar by β-gal. For the α-series, a steric mechanism is in play where the sugar blocks water access to the lanthanide center.
- We report a mechanistic investigation of an isomeric series of β-galactosidase-activated magnetic resonance contrastagents. Our strategy focuses on the synthesis of macrocyclic caged-complexes that coordinatively saturate a chelatedlanthanide. Enzyme cleavage of the complex results in an open coordination site available for water that createsa detectable MR contrast agent. The complexes consist of a DO3A Gd(III) chelator modified with a galactopyranoseat the N-10 position of the macrocycle. We observed significant differences in relaxometric properties and coordinationgeometry that can be correlated to subtle variations of the linker between the macrocycle and the galactopyranose.After synthesis and purification of the R, S, and racemic mixtures of complexes 1 and 3 and measurement of thehydration number, water residence lifetime, and longitudinal relaxation rates, we propose mechanisms for waterexclusion from the lanthanide in the precleavage state. While the stereochemistry of the linker does not influencethe agents' properties, the mechanism of water exclusion for each isomer is significantly influenced by the positionof modification. Data for one series with a methyl group substituted on the sugar-macrocycle linker at the α-positionsuggests a steric mechanism where the galactopyranose sugar blocks water from the Gd(III) center. In contrast,our observations for a second series with methyl substitution at the β position of the sugar-macrocycle linker areconsistent with a mechanism in which a bidentate anion occupies two available coordination sites of Gd(III) in theprecleavage state.
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