Gd(DOTAlaP): exploring the boundaries of fast water exchange in gadolinium-based magnetic resonance imaging contrast agents

Abstract

Here, we describe the synthesis of the single amino acid chelator DOTAlaP and four of its derivatives. The corresponding gadolinium(III) complexes were investigated for their kinetic inertness, relaxometric properties at a range of fields and temperatures, water exchange rate, and interaction with human serum albumin (HSA). Derivatives with one inner-sphere water (q = 1) were determined to have a mean water residency time between 8 and 6 ns in phoshate-buffered saline at 37 °C. The corresponding europium complexes were also formed and used to obtain information on the hydration number of the corresponding coordination complexes. Two complexes capable of binding HSA were also synthesized, of which one, Gd(5b), contains no inner-sphere water, while the other derivative, Gd(4b), is a mixture of ca. 15% q =1 and 85% q = 0. In the presence of HSA, the latter displayed a very short mean water residency time (τM(310) = 2.4 ns) and enhanced relaxivity at intermediate and high fields. The kinetic inertness of Gd(4b) with respect to complex dissociation was decreased compared to its DOTAla analogue but still 100-fold more inert than [Gd(BOPTA)(H2O)](2-). Magnetic resonance imaging in mice showed that Gd(4b) was able to provide 38% better vessel to muscle contrast compared to the clinically used HSA binding agent MS-325.

Scheme 1. Synthetic Scheme for Reported Chelators 3, 4a, 4b, 5a, and 5b

Figure 1

Temperature dependence of the ¹⁷O NMR (11.7 T) reduced transverse relaxation rates of Gd(3) (6.73 mM, left) and Gd(5a) in PBS (4.16 mM, right). The solid line represents a fit to the data to determine the mean water residency time τ_M.

Figure 2

Structures of ibuprofen conjugates Gd(4b) and Gd(5b) reported here, as well as previously reported compound Gd(6).

Figure 3

Relaxivity of HSA-bound Gd(5b) (filled circles) and Gd(4b) (open circles) at pH 7.4, at (A) 10 °C, (B) 25 °C, (C) 37 °C, and (D) 50 °C. The difference between the solid and open circles is the inner-sphere contribution to the Gd(4b) relaxivity, and the solid line is the fit to the data described in the text.

Figure 4

Dechelation of Gd(4b) (filled circles) and Gd(6) (open circles) at pH 3 and 37 °C in the presence of 10 mM citrate. Solid lines represent monoexponential fits of the decomplexation reaction.

Figure 5

Preinjection, as well as 1 min postinjection, coronal images obtained with MS-325 (second from left) and Gd(4b) (right). Gd(4b) shows visibly better contrast in the vena cava, which can be quantified as 38 ± 2% better contrast (vs muscle). The dose of agent, time point, and image windowing was the same for both studies. Kidney (ki) and vena cava (vc) are denoted in the far right image.

Figure 6

Inner-sphere relaxivity of Gd(4b) bound to HSA at two different temperatures (10 and 37 °C) and Larmor frequencies.