Multinuclear Mn(II) united-DOTA complexes with enhanced inertness and high MRI contrast ability

Chelating lability significantly hinders the development of Mn(II)-based magnetic resonance image (MRI) contrast agents. Herein, using 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) as a chelating unit, we show that multinuclear Mn(II) united-DOTA chelates are of up to 69-fold higher inertness than Magnevist, a clinical Gd-based contrast agent. The unusual inertness could be ascribed to the multiplexed uniting of Mn(II) chelates, which is illustrated by a series of controlled studies on model compounds. Besides, molecular longitudinal relaxivities of Mn(II) united-DOTA chelates are 17–167 times higher than those of mononuclear Mn(II) complexes. Dynamic in vivo MRI experiments further reveal that Mn(II) united-DOTA complexes could provide more substantial and persistent contrast enhancement than both Mn-DOTA and Magnevist. Our efforts not only demonstrate that multinuclear Mn(II) united-DOTA complexes are a superior alternative to Gd-based contrast agents, but also highlight the significance of chelate unification as a simple yet powerful strategy for the construction of high-performance Mn(II)-based contrast agents.