High-relaxivity magnetic resonance imaging contrast agents. Part 2. Optimization of inner- and second-sphere relaxivity

摘要: Rationale and objectives The observed relaxivity of gadolinium-based contrast agents has contributions from the water molecule(s) that bind directly to gadolinium ion (inner-sphere water), long-lived molecules exchangeable protons make up second-sphere coordination, diffuse near agent (outer-sphere). Inner- can both be increased by optimization lifetimes in these coordination spheres, rotational motion complex, electronic relaxation ion. We sought identify new high-relaxivity systematically varying donor atoms increase inner-sphere concurrently including substituents influence relaxivity. Methods Twenty gadolinium-1,4,7,10-tetraazacyclo-dodecane-N,N',N″,N'″-tetraacetato derivatives were prepared their determined presence absence human serum albumin as a function temperature magnetic field. Data was analyzed extract underlying molecular parameters influencing Each compound had common albumin-binding group an set comprising 4 tertiary amine N cyclen, α-substituted acetate oxygen atom, 2 amide atoms, variable group. nitrogen substituted with different groups promote hydrogen bonding molecules. Results Relativities at 0.47 1.4 T, 37°C, ranged 16.0 58.1 mM(-1)s(-1) 12.3 34.8 mM(-1)s(-1), respectively. reduction exchange typical could offset incorporating phosphonate or phenolate atom first sphere, resulting higher Amide substitution pendant carboxylate much 88% compared N-methyl analog. Second-sphere contributed 24 14 Conclusions Water/proton dynamics inner- second-coordination sphere predictably tuned choice substituents, agents.