Toward the Design of MR Agents for Imaging β-Cell Function

Abstract

The chemistry of Gd(3+)-based MRI agents has advanced considerably during the past decade toward agents with higher relaxivity and agents that respond to physiology and/or metabolism. This review describes various approaches that have been taken toward the development of responsive contrast agents and discusses the importance of fast water exchange for advancement of targeted Gd(3+)-based agents with higher sensitivity. The recent discovery of Eu(3+) complexes having extraordinarily slow water exchange has opened a new avenue in contrast agent design based upon the chemical exchange saturation transfer (CEST) mechanism. These new paramagnetic complexes called PARACEST agents offer new possibilities of imaging biological functions such as tissue pH and metabolite levels. The lower detection limits that may apply to each class of contrast agent (Gd(3+)-based versus PARACEST) are discussed and the extent to which they may be applied to the imaging of β-cells is considered.

Fig. (1)

Theoretical calculations of relaxivity as a function of the rotational correlation time (τ_R) and the water residence lifetime (τ_M). The upper chart shows the relaxivity obtained if the electronic relaxation time is optimal (τ_S0 = 1ns), the lower chart when a shorter time is employed (τ_S0 = 0.12 ns).

Fig. (2)

The effect of increasing the number of acetates in a complex is clearly seen from the temperature dependence of the ¹⁷O transverse relaxation rates of GdDOTA-4AmP ⁵⁻, GdDOTA-2AmP³⁻ and GdDOTA-1AmP²⁻.

Fig. (3)

The structures of the four stereoisomeric coordination geometries of LnDOTA⁻ complexes and the processes by which they interconvert.

Fig. (4)

The Extended spectral width ¹H NMR spectra of the two isomers S(RRRR) (a) and S(SSSS) (b) NO₂BnDOTMA that adopt SAP and TSAP coordination geometries, respectively. The greater chemical shifts observed in the SAP isomer is characteristic of the more compact structure.

Fig. (5)

Schematic representations of the SAP and TSAP isomers in profile. The effect of the smaller N-C-C-O torsion angle in pushing the acetate oxygens towards the water coordination site can easily be seen.

Fig. (6)

pH dependence of the relaxivity of GdDO3ALA in the presence of carbonate, showing how relaxivity may be quenched by formation of ternary complexes.

Fig. (7)

The crystal structure of YbDO3Ph³⁺ with lactate chelated to the metal center.

Fig. (8)

The cleavage of the galactose moiety in EGad allows water access to the gadolinium(III) ion.

Fig. (9)

The binding of calcium(II) by GdDOPTA results in a change of hydration state at the gadolinium(III) centers “switching on” the inner sphere relaxivity.

Fig. (10)

The binding modes of GdDTPA-BPYED with zinc(II) changes according the zinc concentration.

Fig. (11)

The relaxivity of GdDOTA4AmP⁵⁻ shows a marked pH dependence.

Fig. (12)

A pH map of mice kidneys obtained using GdDOTA4 AmP⁵⁻.

Fig. (13)

The lower detection limit of a contrast agent predicted from the tissue contrast model (TCM) [74]. The imaging field is 500 MHz and the signal to noise ratio has been fixed at 14. It has been assumed that the relaxivity of the agent in region B would remain at a constant 4.5 mM⁻¹s⁻¹. The detection limit is plotted as a function of the relaxivity of the agent in region A for a number of concentration values of the contrast agent in region B.

Fig. (14)

TAFI cleaves the lysine residues from GdDTPA-BIPHEN-TRIK unmasking the biphenyl group which is then able to bind to HSA enhancing relaxivity.

Fig. (15)

Plot of the fractional decrease in bulk water signal intensity expected for a PARACEST agent having a bound water lifetime (τ_M) of 3 µs and a bound water (¹H) paramagnetic shift of 500 ppm (Eqn. 10).

Fig. (16)

CEST images of phantoms containing 10 mM EuDOTA-4AmBBA plus either 0, 5, 10 or 20 mM glucose, which was obtained by subtraction the image by saturating at 50 ppm from that at 30 ppm [101]

Fig. (17)

Mn²⁺-enhanced T₁-weighted contrast of rat pancreatic islets. Two capillary tubes containing pancreatic-islets were incubated for 30 minutes in the presence of 25 mM MnCl₂. The tubes were incubate in 5 mM glucose (left) and 20 mM glucose (right). The image was acquired at 500 MHz with TR = 400 ms, TE = 7.2 ms, slice thickness = 100 mm, field-of-view = 4.8 mm × 2.4 mm, acquisition matrix = 128 × 64, and number of averages = 64. Reproduced with permission from reference [115].

Chart 1

The structures of contrast agents currently approved for clinical use and MS-325, an agent under development.

Chart 2

The structures of some gadolinium chelates that exhibit more rapid water exchange rates.

Chart 3