Hexameric Mn(II) dendrimer as MRI contrast agent

Abstract

A Mn(II) chelating dendrimer was prepared as a contrast agent for MRI applications. The dendrimer comprises six tyrosine-derived [Mn(EDTA)(H2 O)](2-) moieties coupled to a cyclotriphosphazene core. Variable temperature (17) O NMR spectroscopy revealed a single water co-ligand per Mn(II) that undergoes fast water exchange (kex =(3.0±0.1)×10(8) s(-1) at 37 °C). The 37 °C per Mn(II) relaxivity ranged from 8.2 to 3.8 mM(-1) s(-1) from 0.47 to 11.7 T, and is sixfold higher on a per molecule basis. From this field dependence a rotational correlation time was estimated as 0.45(±0.02) ns. The imaging and pharmacokinetic properties of the dendrimer were compared to clinically used [Gd(DTPA)(H2 O)](2-) in mice at 4.7 T. On first pass, the higher per ion relaxivity of the dendrimer resulted in twofold greater blood signal than for [Gd(DTPA)(H2 O)](2-) . Blood clearance was fast and elimination occurred through both the renal and hepatobiliary routes. This Mn(II) containing dendrimer represents a potential alternative to Gd-based contrast agents, especially in patients with chronic kidney disease where the use of current Gd-based agents may be contraindicated.

Keywords: NMR spectroscopy; dendrimers; imaging agents; magnetic resonance imaging; manganese.

Figure 1

$r_2^O$ of the monomeric (circles) and dendrimeric (triangles) Mn(II) complexes as a function of temperature. Solid lines represent fits to the data. The hydration state and water exchange parameters are virtually unchanged upon incorporation of the monomer into the hexameric dendrimer.

Figure 2

Inner-sphere per Mn(II) r₁ of the monomer (circles) and dendrimer (triangles) as a function of applied magnetic field. Inner-sphere contribution to r₁ estimated by subtracting the relaxivity of [Mn(DTPA]³⁻ from the observed relaxivity of the dendrimer. The solid line represents a best fit to the data, see text.

Figure 3

Coronal images of the chest of a mouse acquired pre- and 1, 10, and 25 minutes post-injection of [Gd(DTPA)(H₂O)]²⁻ and dendrimeric Mn (II) chelate. Selected slice shows the heart and jugular vein and demonstrates dramatic signal enhancement of the blood pool immediately after injection, but rapid washout with time. At one minute post injection [Gd(DTPA)(H₂O)]²⁻ gave a 260±80% increase in vascular signal-to-noise ratio (SNR) compared to baseline (N=4), while the Mn(II) dendrimer increased SNR 510±70%, a 2-fold improvement over [Gd(DTPA)(H₂O)]²⁻.

Figure 4

Time course of signal intensity in the heart (empty arrowhead), liver (beneath heart), kidneys (filled arrowheads), and gallbladder (arrow) following injection of the Mn(II) dendrimer. The signal in the blood and kidneys is high post injection but decreases rapidly with time as the compound clears into the urine. Strong signal enhancement that washes out with time is also evident in the liver. Gallbladder signal grows with time demonstrating hepatobiliary clearance. The image obtained one minute post injection was acquired with lower spatial resolution (0.375 mm³ isotropic) to allow sampling of peak vascular enhancement with higher temporal resolution. The images at later time points were obtained with 0.25mm³ spatial resolution.

Scheme 1

Monomeric Mn(II) chelate and hexameric dendimer.

Scheme 2

Synthesis of monomeric and dendrimeric Mn(II) ligands.