Synthesis and Relaxivity Studies of a Gadolinium(III) Complex of ATP‐Conjugated DO3A as a Contrast Enhancing Agent for MRI

Abstract

AbstractA gadolinium(III) complex of adenosine 5′‐triphosphate (ATP)‐appended DO3A has been synthesized in order to attain higher relaxivity and to reduce the in vivo toxicity. DO3A (2) was synthesized as the exclusive product by a single step direct trialkylation of cyclen with chloroacetic acid in water (pH 10, –4 °C). ATP was then covalently appended to the DO3A framework through a propyl linker. The 3‐bromopropane spacer appended DO3A (3) was synthesized by the reaction of DO3A with 1,3‐dibromopropane in water/DMF in the presence of triethylamine as proton scavenger. The ATP‐appended DO3A (DO3A‐Pr‐ATP) was synthesized by the reaction of 3 with ATP in water at room temperature. [Gd(DO3A‐Pr‐ATP)(H2O)2] (4) was synthesized by the reaction of DO3A‐Pr‐ATP with gadolinium(III) perchlorate hydrate in water. The X‐ and Q‐band EPR spectra of 4 contain a broad band with no hyperfine splitting at both room temperature and liquid nitrogen temperature. The g‐values are 2.167 and 2.033 at X‐ and Q‐band, respectively. The magnetic moment of 4 is 7.45 BM which is close to the value for free GdIII ion. The longitudinal relaxivity, r1p, of [Gd(DO3A‐Pr‐ATP)(H2O)2] is 6.51 mM–1 s–1 (24 MHz and 35 ± 0.1 °C), which is higher than that of [Gd(DOTA)(H2O)]– (r1p = 3.56 mM–1 s–1, 20 MHz, 39 °C, pH 7.3) and [Gd(DO3A)(H2O)2] (r1p = 4.8 mM–1 s–1, 20 MHz, 40 °C). The higher relaxivity of 4 than for other systems with q = 2 is due to the increase in the molecular dimension of the complex by the conjugation of ATP. The relaxivity of 4 at pH 8.4 (TRIS buffer) decreases to 5.64 mM–1 s–1, probably due to a change in the hydration number by the replacement of the coordinated water molecules by TRIS. The r1p relaxivity of 4 in the presence of β‐cyclodextrin is 8.97 mM–1 s–1 due to the increase in the molecular weight and dimension of the inclusion complex formed by the noncovalent host–guest interaction of the ATP pendant arm with the hydrophobic cavity of β‐cyclodextrin. The transverse relaxivity, r2p, of 4 is 7.48 mM–1 s–1 (24 MHz and 35 ± 0.1 °C). The r2p/r1p ratio of 1.16 indicates that 4 is a T1‐weighted contrast agent. The ATP moiety remains as an extended pendant arm and does not bind with the metal ion, nor does it block the coordination sites for the inner‐sphere water molecules. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)