Near infrared-fluorescent and magnetic resonance imaging molecular probe with high T1 relaxivity for in vivo multimodal imagingw

Integration of optical and magnetic resonance imaging (MRI) methods in one setting is appealing due to the complementary nature of MRI’s high spatial and temporal resolution and the high molecular sensitivity of optical imaging. In particular, deep tissue penetration of near-infrared (NIR) photons and minimal autofluorescence in this wavelength range favors the assessment of molecular events in thick tissue by optical in vivo imaging. A major challenge in constructing dual MRI/optical probes is matching the relatively low contrast agent’s detection sensitivity (micromolar) by MRI with the single molecule detection capability of fluorescence imaging. Herein, we report a new molecular design consisting of a Gd chelating NIR carbocyanine dye (LS-479–Gd; Fig. 1) to bridge the sensitivity gap between the two imaging modalities. We envisioned that MRI sensitivity could be improved by decreasing the rotational diffusion of the molecular probe, which could be achieved by anchoring the probe to a macromolecule such as a protein. With this dual Gd–fluorophore probe, we were able to obtain high T1 weighted MRI and fluorescence imaging contrast in small animals. MRI produces high spatial resolution images of soft tissue by measuring the relaxation rate of water protons. With their high magnetic moment, paramagnetic lanthanide ions increase the relaxation rate of proximal protons and provide contrast. High relaxivity translates into improved detection sensitivity at relatively lower contrast agent concentration than is traditionally used for MRI. Gd is the most commonly used MRI contrast agent due to its optimal electronic characteristics. The high toxicity of free Gd requires its incorporation in a chelating matrix, hence a variety of gadolinium chelates have been developed, either as nonspecific extracellular agents or as targeted agents optimized for specific medical applications. In general, total relaxivity of an MRI contrast agent depends on a number of factors, including rate of water exchange and its rotational diffusion. Total relaxivity is a combination of inner and outer sphere relaxivities. The inner sphere relaxivity is given by the following equation: