T2 exchange agents: A new class of paramagnetic MRI contrast agent that shortens water T2 by chemical exchange rather than relaxation

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8568, USA.
Magnetic Resonance in Medicine (Impact Factor: 3.4). 12/2011; 66(6):1697-703. DOI: 10.1002/mrm.22938
Source: PubMed

ABSTRACT Exchange of water molecules between the frequency-shifted inner-sphere of a paramagnetic lanthanide ion and aqueous solvent can shorten the T(2) of bulk water protons. The magnitude of the line-broadening T(2) exchange (T(2exch)) is determined by the lanthanide concentration, the chemical shift of the exchanging water molecule, and the rate of water exchange between the two pools. A large T(2exch) contribution to the water linewidth was initially observed in experiments involving Eu(3+)-based paramagnetic chemical exchange saturation transfer agents in vivo at 9.4 T. Further in vitro and in vivo experiments using six different Eu(3+) complexes having water exchange rates ranging from zero (no exchange) to 5 × 10(6) s(-1) (fast exchange) were performed. The results showed that the exchange relaxivity (r(2exch)) is small for complexes having either very fast or very slow exchange, but reaches a well-defined maximum for complexes with intermediate water exchange rates. These experimental results were verified by Bloch simulations for two site exchange. This new class of T(2exch) agent could prove useful in the design of responsive MRI contrast agents for molecular imaging of biological processes.

  • [Show abstract] [Hide abstract]
    ABSTRACT: PurposeDemonstrate applicability of natural D-glucose as a T2 MRI contrast agent.MethodsD-glucose solutions were prepared at multiple concentrations and variable pH. The relaxation rate (R2 = 1/T2) was measured at 3, 7, and 11.7 T. Additional experiments were performed on blood at 11.7 T. Also, a mouse was infused with D-glucose (3.0 mmol/kg) and dynamic T2 weighted images of the abdomen acquired.ResultsThe transverse relaxation rate depended strongly on glucose concentration and solution pH. A maximum change in R2 was observed around physiological pH (pH 6.8-7.8). The transverse relaxivities at 22°C (pH 7.3) were 0.021, 0.060, and 0.077 s−1mM−1 at 3.0, 7.0, and 11.7 T, respectively. These values showed good agreement with expected values from the Swift-Connick equation. There was no significant dependence on glucose concentration or pH for T1 and the diffusion coefficient for these solutions. The transverse relaxivity in blood at 11.7 T was 0.09 s−1mM−1. The dynamic in vivo experiment showed a 10% drop in signal intensity after glucose infusion followed by recovery of the signal intensity after about 50–100 s.Conclusion Glucose can be used as a T2 contrast agent for MRI at concentrations that are already approved for human use. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.
    Magnetic Resonance in Medicine 09/2014; 72(3). DOI:10.1002/mrm.25329 · 3.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A series of 1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate monoamide (DO3A-monoanilide) complexes Dy3+ and Tm3+ were prepared and their magnetic properties evaluated in the context of their potential use as pH sensors. The ligands varied by para-substitution of the aniline moiety and represent electron-withdrawing and electron-donating groups. Only the Tm3+ complexes produced chemical exchange saturation transfer (CEST) spectra with CEST intensities due to the amide proton ranging from 1% to 8%. A maximum CEST signal was observed under slightly alkaline conditions (pH ∼8) when electron-donating groups were present, whereas the strongly electron-withdrawing nitro group produced a maximum CEST at neutral pH (pH = 7). The T 1 and T 2 relaxivities of the Dy3+ and Tm3+ complexes were also assessed. The T 1 relaxivities of the Dy3+ and Tm3+ complexes were both low (r 1 ≤ 0.3 mM−1 s−1, 25 °C, pH = 7) but, as expected, the Dy3+ complexes had much higher T 2 relaxivities (r 2 = 2–7 mM−1 s−1, 25 °C, pH = 7) as compared to the Tm3+-based chelates (r 2 ≤ 0.09 mM−1 s−1, 25 °C, pH = 7).
    Canadian Journal of Chemistry 01/2014; 93(2-2):244-252. DOI:10.1139/cjc-2014-0314 · 1.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Magnetic resonance imaging (MRI) enables high-resolution non-invasive observation of the anatomy and function of intact organisms. However, previous MRI reporters of key biological processes tied to gene expression have been limited by the inherently low molecular sensitivity of conventional (1)H MRI. This limitation could be overcome through the use of hyperpolarized nuclei, such as in the noble gas xenon, but previous reporters acting on such nuclei have been synthetic. Here, we introduce the first genetically encoded reporters for hyperpolarized (129)Xe MRI. These expressible reporters are based on gas vesicles (GVs), gas-binding protein nanostructures expressed by certain buoyant microorganisms. We show that GVs are capable of chemical exchange saturation transfer interactions with xenon, which enables chemically amplified GV detection at picomolar concentrations (a 100- to 10,000-fold improvement over comparable constructs for (1)H MRI). We demonstrate the use of GVs as heterologously expressed indicators of gene expression and chemically targeted exogenous labels in MRI experiments performed on living cells.
    Nature Chemistry 07/2014; 6(7):629-34. DOI:10.1038/nchem.1934 · 23.30 Impact Factor