Gadolinium complexes of monophosphinic acid DOTA derivatives conjugated to cyclodextrin scaffolds: efficient MRI contrast agents for higher magnetic fields

Abstract

Middle-molecular-weight MRI contrast agents based on conjugates of a phosphinic acid DOTA analogue, 1,4,7,10-tetraazacyclododecane-4,7,10-triacetic-1-{methyl[(4-aminophenyl)methyl]phosphinic acid} (DO3AP(ABn)), with amino-substituted cyclodextrins were prepared and studied by a variety of physico-chemical methods. The conjugates were formed by reaction of the corresponding isothiocyanate with per-6-amino-α/β-cyclodextrin and were complexed with the Ln(III) ion to get the final complexes, (LnL)(6)-α-CD and (LnL)(7)-β-CD. Solution structure of the complexes was estimated by investigation of the Eu(III) complexes. The Gd(III) conjugate complexes are endowed with a short water residence time (τ(M) ∼ 10-15 ns at 298 K) and a high abundance of the twisted-square antiprismatic diastereoisomer. They show a high (1)H relaxivity at high fields due to a convenient combination of the fast water exchange rate and the slow rate of the molecular tumbling given by their macromolecular nature. The (1)H relaxation enhancements per molecule of a contrast agent (CA) are very high reaching for a larger (GdL)(7)-β-CD conjugate ∼140 s(-1) mM(-1) and ∼100 s(-1) mM(-1) at 25 °C and magnetic fields 1.5 T and 3 T, respectively, which is the highest reported longitudinal relaxivity for kinetically stable contrast agents of an intermediate molecular mass (<10 kDa) with one water molecule in the first coordination sphere.