In vivo magnetic resonance imaging of Eu-based PARACEST contrast agents using SWIFT

Introduction Paramagnetic chemical exchange saturation transfer (PARACEST) agents use water molecule exchange with lanthanide ions (Ln) and radiofrequency (RF) spin saturation to create negative contrast in MRI [1]. If the rate of exchange between the bound and bulk water locations is much slower than their frequency difference (i.e. kex << Δω) then RF spin saturation at the shifted bound water frequency (Δω) will cause indirect partial saturation of the bulk water signal through chemical exchange [2]. One advantage that PARACEST agents have over Gd-based T1 agents is that image contrast can be turned off and on via the RF saturation pulse frequency. Some published applications of PARACEST include measures of tissue pH [3], Zn ion concentration [4], beta-cell function [5], and the tissue distribution of glucose [6]. We have recently shown that chemical exchange of water molecules between Eu-based PARACEST agents and bulk water can also facilitate T2 exchange (T2exch) [7, 8]. T2exch causes a significant reduction in the bulk water T2 (i.e. negative contrast) for agents with high local concentrations, intermediate exchange rates, and large chemical shifts. The negative contrast is present even when the RF saturation pulse is omitted, causing the PARACEST agents to behave like susceptibility or T2 agents. A current challenge for in vivo imaging of PARACEST agents is that a significant T2exch contribution can make the regions of agent uptake appear dark in both the “Off” (saturation at -Δω) and “On” (saturation at Δω) images when using conventional sequences like gradient-echo and fast spin-echo [7-9]. The minimum TE for these sequences (1 to 10 ms) is not short enough to capture signal from the regions of reduced T2 making CEST imaging (“Off”-“On”) difficult. We hypothesized that the ultra-short TE (<10 μs) used in the sweep imaging with Fourier transform (SWIFT) sequence [10] could reclaim the loss in signal due to T2exch and enable fast and sensitive in vivo PARACEST imaging. We investigated this hypothesis at 9.4 T using a EuDOTA(gly)4 PARACEST agent and the SWIFT Launch Kit from Steady State Imaging. Materials and Methods In vivo mouse data were acquired on a Varian 9.4 T small animal MRI system using the SWIFT-compatible 27 mm diameter surface coil and software (beta version 580) from Steady State Imaging. Images were acquired at 37 C using the SWIFT pulse sequence (TR/TE = 1.23 ms/<10 μs, averages = 1, dummy scans = 512, np = 128, views/spirals = 8192/4, sw = 125 kHz, FOV = 50 mm, resolution = 0.39 mm). The SWIFT “fatsat” function was used to create a 0.5 second long, 20 μT saturation pulse for each nturbo (64 views). The total scan time for each image was 5 minutes. A 1.0 mmol/kg dose of EuDOTA-(gly)4 was administered in 200 μL to the healthy mouse via tail vein injection immediately before imaging. Results