Myelin Imaging Compound (MIC) Enhanced Magnetic Resonance Imaging of Myelination

Abstract

The vertebrate nervous system is characterized by myelination, a fundamental biological process that protects the axons and facilitates electric pulse transduction. Damage to myelin is considered a major effect of autoimmune diseases such as multiple sclerosis (MS). Currently, therapeutic interventions are focused on protecting myelin integrity and promoting myelin repair. These efforts need to be accompanied by an effective imaging tool that correlates the disease progression with the extent of myelination. To date, magnetic resonance imaging (MRI) is the primary imaging technique to detect brain lesions in MS. However, conventional MRI cannot differentiate demyelinated lesions from other inflammatory lesions, and therefore cannot predict disease progression in MS. To address this problem, we have prepared a Gd-based contrast agent, termed MIC (Myelin Imaging Compound), which binds to myelin with high specificity. In this work, we demonstrate that MIC exhibits a high kinetic stability towards transmetallation with promising relaxometric properties. MIC was used for in vivo imaging of myelination following intracerebroventricular infusion in the rat brain. MIC was found to distribute preferentially in highly myelinated regions and was able to detect regions of focally induced demyelination.

Enhanced characterization of the zebrafish brain as revealed by super-resolution track-density imaging

“…As a result, researchers rely on a variety of pulse sequences to exploit variations in either proton density and tissue relaxation properties (Johnson et al 2010;McLaren et al 2009;Johnson et al 2012), and/or a limited number of contrast agents. To date the majority of studies have utilized gadolinium-based contrast agents, such as Magnevist® and Pro-Hance®, however Manganese, a functional contrast agent (Koretsky and Silva 2004) (Leergaard et al 2003), and more recently potassium dichromate (Rowland 2011;Zhang et al 2010) and myelin-specific (Frullano et al 2012) contrast agents have also been used.…”

Strategies for Target-Specific Contrast Agents for Magnetic Resonance Imaging

“…Hence, the synthesis of targeting biomarkers to image neuropathology with MRI is an active area of research because of the current lack of in vivo detection methods. β-Amyloid peptides and myelin are two components that have been investigated as targets [35–39]. …”

“…Wang and coworkers reported myelin-targeted contrast agent 14 (Fig. 2) [38, 39]. Contrast agent 14 contains a coumarine derivative as the targeting unit conjugated to Gd III DOTA, and this agent has a relaxivity of 5.2 mM −1 s −1 (9.4 T, 21 °C, and water).…”

“…Subsequent in vivo studies were carried out with intracerebroventricular infusions (~1 mg (1.14 μmol)/kg) because of the poor BBB penetration of 14 . These studies demonstrated the specificity for myelin and the ability of 14 to highlight demyelination with T 1 mapping at 9.4 T [39]. However, conventional MR imaging was not reported with this agent, which likely was due to low sensitivity that needs to be improved for clinical translations of 14 .…”

Myelin‐targeted, texaphyrin‐based multimodal imaging agent for magnetic resonance and optical imaging

“…Myelin‐specific contrast agents provide a way to augment the lack of specificity when imaging myelin. Myelin‐specific Gd III ‐containing small molecules were reported that are similar in efficiency to nonspecific clinically approved contrast agents . These contrast agents that have longitudinal relaxivity ( r 1 ) of ~5.1 mM –1 s –1 at 1.41 T were able to highlight myelination in MRI via T 1 maps; however, the images acquired with these agents demonstrate the need for contrast agents with higher relaxivity values to produce images of myelinated structures with increased signal‐to‐noise ratios .…”