Proton Relaxation Properties of a Particulate Iron Oxide MR Contrast Agent in Different Tissue Systems : Implications for Imaging

Knowledge of the relationship between in vivo contrast agent concentration and magnetic resonance (MR) signal response is an important requirement in contrast enhanced MR imaging in general and in MR based perfusion imaging in particular. This relationship is a complex function of the properties of the contrast agent as well as the structure of the target tissue. The aim of the present work was to quantify the effects of the iron oxide nanoparticle based intravascular contrast agent, NC100150 Injection, on proton relaxation rates in different tissue systems in vivo in a pig model and ex vivo in phantoms containing whole blood. Methods that enabled accurate relaxation rate measurements in these organs were developed, and validated. From these measurements, trans-compartmental water exchange rates and blood volume could be estimated and the MR signal response could be predicted as a function of contrast agent concentration under relevant imaging conditions. Using a 1.5 Tesla clinical MR system, the longitudinal (R1=1/T1) proton relaxation rates in blood, renal cortex, paraspinal muscle and myocardium were measured in vivo as a function of plasma concentration (Cp) of NC100150 Injection. The transverse (R2* = 1/T2*) relaxation rates were measured in vivo in blood, renal cortex and muscle as a function of Cp and ex vivo in blood as a function of Cp and blood oxygenation tension. The proton nuclear MR (NMR) linewidth and lineshape were analysed as a function of Cp and blood oxygen tension ex vivo at 7.05 T. In muscle and renal cortex, there was a linear correlation between R2* and Cp whereas R2* increased as a quadratic function of Cp in blood. The NMR linewidth increased linearly with Cp in fully oxygenated blood whereas in deoxygenated blood the linewidth initially decreased with increasing Cp, reaching a minimum and then increasing again with further increase in Cp. R1 increased linearly with Cp in blood and from the slope of R1 vs. Cp the T1-relaxivity (r1) of NC100150 Injection in blood at 1.5 T was estimated to be (mean ± SD) 13.9 ± 0.9 s-1mM-1. In tissue, the maximum increase in R1 was limited by the rate of water exchange between the intravascular and interstitial tissue compartments. Using a two-compartment exchange-limited relaxation model, the permeability surface area (PS) product was estimated to be 61.9 ± 2.9 mL/min/g in renal cortex and 10.1 ± 1.5 mL/min/g in muscle and the total myocardial water exchange rate, kt, was 13.5 ± 6.4 s-1. The estimated blood volumes obtained from the same model were 19.1 ± 1.4 mL/100 g, 2.4 ± 1.4 mL/100 g and 11.2 ± 2.1 mL/100 g, respectively in renal cortex, muscle and myocardium. Current T2* based first-pass MR perfusion methods assume a linear correlation between R2* and Cp both in blood and tissue and our results therefore suggest that quantitative perfusion values can not easily be obtained with existing tracer kinetic models. The correlation between MR signal response and Cp is further complicated in the kidney by a significant first-pass increase in R1 which may lead to an underestimation of Cp. In T1-based perfusion methods, low concentrations of NC100150 Injection must be used in order to maintain a linear dose-response relationship between R1 and Cp. The effect of blood oxygenation on the NMR linewidth in the presence of NC100150 Injection enabled accurate estimation of magnetic susceptibility of deoxyhemoglobin and the effect can potentially be used to determine blood oxygenation status. In conclusion, NC100150 Injection is well suited as a T2* perfusion agent due to the large magnetisation and intravascular biodistribution of this agent. T1-based perfusion imaging with this agent is limited by water exchange effects and large T2* effects at higher contrast agent concentrations. Quantitative perfusion assessment is unlikely to be feasible with any of these approaches due to the non-linear dose response