In vivo detection of MRI‐PARACEST agents in mouse brain tumors at 9.4 T

Abstract

Paramagnetic chemical exchange saturation transfer (PARACEST) contrast agents are under development for biological target identification by magnetic resonance imaging. Image contrast associated with PARACEST agents can be generated by radiofrequency irradiation of the chemically shifted protons bound to a PARACEST contrast agent molecule or by direct irradiation of the on-resonance bulk water protons. The observed signal change in a magnetic resonance image after the administration of a PARACEST contrast agent is due to both altered relaxation time constants and the CEST effect. Despite high sensitivity in vitro, PARACEST agents have had limited success in vivo where sensitivity is reduced by the magnetization transfer effect from endogenous macromolecules. The purpose of this study was to demonstrate the in vivo detection of a PARACEST contrast agent using the on-resonance paramagnetic chemical exchange effect (OPARACHEE) in a mouse glioblastoma multiforme tumor model and to isolate the OPARACHEE effect from the changes in relaxation induced by the PARACEST agent. Three mice with tumors were imaged on a 9.4 T MRI scanner following tail vein injection of 150 μL 50 mM Tm(3+)-DOTAM-glycine-lysine. A fast low angle shot pulse sequence with a low power radiofrequency pulse train (WALTZ-16) as the preparation pulse was used to generate OPARACHEE contrast. To study the dynamics of agent uptake, reference images (without the preparation pulse) and OPARACHEE images were acquired continuously in an alternating fashion before, during and after agent injection. Signal intensity decreased by more than 10% in tumor in the control images after agent administration. Despite these changes, a clear OPARACHEE contrast of 1-5% was also observed in brain tumors after contrast agent injection and maintained in the hour following injection. This result is the first in vivo observation of OPARACHEE contrast in brain tumors with correction of T(1) and T(2) relaxation effects.