In Vivo Cleavage Rate of a Dextran-bound Magnetic Resonance Imaging Contrast agent: Preparation and Intravascular Pharmacokinetic Characteristics in the Rabbit

Petter      Arnt Hals; Per      Christian Sontum; Eckart      Holtz; Jo      Klaveness; Pal      Rongved

doi:10.2174/1567201811310010019

Abstract

Earlier described dextran-based contrast agents for magnetic resonance imaging (MRI) comprising the gadolinium chelate diethylenetriamine pentaacetic acid (GdDTPA, 1) have shown significantly shorter in vivo contrast duration in rat than what would be expected from the initial average molecular weight (Mw) of the dextran fraction (71.4 kD). To investigate this further, four dextran fractions with given initial average molecular weight (Mw) of 10.4, 41.0, 71.4 and 580 kD were used as starting material to prepare products 2-5 where one of the carboxylic acid functionalities in GdDTPA was used as a direct covalent ester linker to hydroxyl groups in dextrans. A fifth derivative (6) was an amide-ester bound β-alanine-DTPAGd conjugate with dextran having Mw 71.4 kD. The reference compound GdDTPA (1) and gadoliniumlabelled dextran derivatives 2-6 were injected intravenously in rabbits. Pharmacokinetic parameters showed that when GdDTPA is ester-bound directly to dextran hydroxyls, the cleavage rates of 2-5 were only moderately dependent on the molecular weights of the dextrans, having blood pool half-lives comparable to the low-molecular reference compound (t 1/2,β 0.3 – 0.5 hrs.). Presence of a β-alanine spacer in 6 prolonged the plasma half-life t 1/2,β to 6.9 hours, rendering a blood residence time suitable for blood pool slow release of GdDTPA. Biological cleavage regenerates the clinically acceptable carrier dextran and the β-alanine derivative of GdDTPA, pointing at a clinically acceptable product class for blood-pool contrast in MRI.

Keywords: Magnetic resonance imaging, contrast agent, carrier –dextran, pharmacokinetics, rabbit

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