Single Molecule Eu^2+/3+ Complex Platform for Optical and Magnetic Resonance Imaging In Vivo

Lanthanide coordination complexes are harnessed for biological imaging due to their oxidative stability in aqueous media, favorable relaxometric behavior, and accessible luminescence emissions within biomedically relevant, optical-imaging wavelength ranges. In contrast with multimodal imaging strategies that rely on exchanging lanthanide ions to access distinct modalities, we exploit the unique redox chemistry of the Eu^2+/3+ pair to demonstrate the feasibility of multimodal imaging within a single chelate scaffold. We constructed a series of polypyridine-containing macrocyclic ligands that readily coordinate both Eu²⁺ and Eu³⁺ ions. Characterization of the corresponding chelates by X-ray crystallography, cyclic voltammetry, electron paramagnetic resonance spectroscopy, and photophysical measurements were conducted. The Eu²⁺-containing complexes of acetamide-functionalized, polypyridine-containing 18-membered macrocycles exhibit relaxometric properties comparable to clinical Gd³⁺ contrast agents for magnetic resonance imaging. Upon oxidation to Eu³⁺, the complexes display characteristic luminescence with quantum yields ranging from 1.3 to 13.9%. In situ sensitization with a Cherenkov-emitting radionuclide efficiently produces Eu³⁺ emission at concentrations comparable to those employed for Eu²⁺-enhanced magnetic resonance imaging. The complex that provided the greatest signal-to-noise ratio in magnetic resonance in vitro imaging studies, and when oxidized, produced a detectable, optical imaging signal with as little as 5 nmol of complex. A subsequent study in a murine xenograft tumor model demonstrated the feasibility of conducting sequential magnetic resonance and optical imaging experiments following single dose administration of the redox-switchable complex.