Physical Properties of Eu(2+)-Containing Cryptates as Contrast Agents for Ultra-High Field Magnetic Resonance Imaging

Abstract

The kinetic stabilities and relaxivities of a series of Eu(2+)-containing cryptates have been investigated. Transmetallation studies that monitored the change in the longitudinal relaxation rate of water protons in the presence of Ca(2+), Mg(2+), and Zn(2+) demonstrated that cryptate structure influences stability, and two of the cryptates studied were inert to transmetallation in the presence of these endogenous ions. The efficacy of these cryptates was determined at different magnetic field strengths, temperatures, and pH values. Cryptate relaxivity was found to be higher at ultra-high field strengths (7 and 9.4 T) relative to clinically relevant field strengths (1.4 and 3 T), but the efficiency of these cryptates decreased as temperature increased. In addition, variation in pH did not yield significant changes in the efficacy of the cryptates. These studies establish a foundation of important properties that are necessary to develop effective positive contrast agents for magnetic resonance imaging from Eu(2+)-containing cryptates.

Figure 1

Evolution of R₁^p(t)/R₁^p(t=0) versus time for the Eu²⁺-containing cryptates Eu–1 (◇) and Eu–2 (□) (2.5 mM) in the presence of Ca²⁺ (2.5 mM). The value 0.8 on the y-axis is the threshold for the kinetic index. Error bars represent standard error of the mean.

Figure 2

Evolution of R₁^p(t)/R₁^p(t=0) versus time for the Eu²⁺-containing cryptates Eu–1 (◇) and Eu–2 (□) (2.5 mM) in the presence of Mg²⁺ (2.5 mM). The value 0.8 on the y-axis is the threshold for the kinetic index. Error bars represent standard error of the mean.

Figure 3

Evolution of R₁^p(t)/R₁^p(t=0) versus time for the Eu²⁺-containing cryptates Eu–1 (◇) and Eu–2 (□) (2.5 mM) in the presence of Zn²⁺ (2.5 mM). The value 0.8 on the y-axis is the threshold for the kinetic index. Error bars represent standard error of the mean.

Figure 4

Contributing resonance structures of cryptands 3 and 4.

Figure 5

Proton longitudinal relaxivity (T = 20 °C, pH = 7.4) of GdDOTA (○) and Eu²⁺-containing cryptates Eu–1 (◇) and Eu–2 (□) as a function of magnetic field strength. Values at 3, 7, and 11.7 T are from reference . Error bars represent standard error of the mean.

Figure 6

Proton longitudinal relaxivity (T = 37 °C, pH = 7.4) of GdDOTA (○) and Eu²⁺-containing cryptates Eu–1 (◇) and Eu–2 (□) as a function of magnetic field strength. Values at 1.4 and 11.7 T are from reference . Error bars represent standard error of the mean.

Figure 7

Proton longitudinal relaxivity (9.4 T and pH = 7.4) of Eu²⁺-containing cryptates Eu–1 (□) and Eu–2 (cir;) as a function of temperature. Error bars represent standard error of the mean.

Figure 8

Proton longitudinal relaxivity (11.7 T, pH = 7.4) of Eu²⁺-containing cryptates Eu–1 (□) and Eu–2 (cir;) as a function of temperature. Error bars represent standard error of the mean.

Figure 9

Longitudinal relaxivity at 1.4 T at 37 °C (Eu–1 (■) and Eu–2 (●)) and 7 T at 19 °C (Eu–1 (□) and Eu–2 (cir;)) as a function of pH. Error bars represent standard error of the mean.

Scheme 1

Structures of cryptands 1–4.

Scheme 2

Synthetic route to cryptands 3 and 4.