A Terbium-Based PARACEST MR Contrast Agent for in Vivo Imaging Beyond the MT Effect

Todd C. Soesbe¹, Federico A. Rojas-Quijano¹, A. Dean Sherry^1,2

Chemical exchange saturation transfer (CEST) agents create contrast in MR images by exchanging their saturated lanthanide bound protons with unsaturated bulk water protons. CEST agents can be selectively activated by applying a 2 to 10 second long frequency-specific saturation pulse, tuned to the bound proton frequency, just before imaging. Chemical exchange of the saturated bound protons with bulk water leads to a reduced water signal and darkening in the MR image. These agents hold great potential to further extend the functional and molecular imaging capabilities of MR. Some published applications include measuring tumor pH, angiogenesis, and the tissue distribution of glucose and other metabolites. CEST agent bound proton frequencies are typically shifted 5 to 50 ppm from bulk water (0 ppm). Unfortunately, this is the same range of the in vivo Magnetization Transfer (MT) effect. The MT effect arises from dipolar exchange of protons with endogenous tissue materials such as macromolecules and cell membranes. The MT effect typically spans from 100 ppm (relative to bulk water) and is proportional to saturation pulse power. As a consequence, the contrast produced by the CEST agent can be totally masked by the tissue MT effects, which greatly complicates in vivo imaging. In an effort to avoid the MT effect and enhance in vivo CEST imaging, our group has recently developed a Tb3+-based paramagnetic CEST (PARACEST) agent with an unusually long bound water exchange lifetime. The bound proton frequency for this agent is at -600 ppm, which is far outside the normal tissue MT window. Although other Tb3+-based PARACEST agents have been reported, this agents slower water exchange rate allows for an order of magnitude reduction in saturation pulse power, making it more suitable for in vivo studies. We present in vitro images of our Tb3+-based PARACEST agent to demonstrate its potential for in vivo imaging without the requirement of subtracting out tissue MT contributions.