Bifunctional Chelates Optimized for Molecular MRI

Important requirements for exogenous
dyes or contrast agents in
magnetic resonance imaging (MRI) include an effective concentration
of paramagnetic or superparamagnetic ions at the target to be imaged.
We report the concise synthesis and characterization of several new
enantiopure bifunctional derivatives of (α1R,α4R,α7R,α10R)-α1,α4,α7,α10-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
acid (DOTMA) (and their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic
acid (DOTA) analogues as controls) that can be covalently attached
to a contrast agent delivery system using either click or peptide
coupling chemistry. Gd complexes of these derivatives can be attached
to delivery systems while maintaining optimal water residence time
for increased molecular imaging sensitivity. Long chain biotin (LC-biotin)
derivatives of the Eu­(III) and Gd­(III) chelates associated with avidin
are used to demonstrate higher efficiencies. Variable-temperature
relaxometry, 17O NMR, and nuclear magnetic resonance dispersion
(NMRD) spectroscopy used on the complexes and biotin–avidin
adducts measure the influence of water residence time and rotational
correlation time on constrained and unconstrained systems. The Gd­(III)-DOTMA
derivative has a shorter water residence time than the Gd­(III)-DOTA
derivative. Compared to the constrained Gd­(III)-DOTA derivatives,
the rotationally constrained Gd­(III)-DOTMA derivative has ∼40%
higher relaxivity at 37 °C, which could increase its sensitivity
as an MRI agent as well as reduce the dose of the targeting agent.