In vivo MRI assessment of a novel Gd^III‐based contrast agent designed for high magnetic field applications

Abstract

Gd(3)L is a trinuclear Gd(3+) complex of intermediate size, designed for contrast agent applications in high field magnetic resonance imaging (H(12)L is based on a trimethylbenzene core bearing three methylene-diethylenetriamine- N,N,N'',N''-tetraacetate moieties). Thanks to its appropriate size, the presence of two inner sphere water molecules and a fast water exchange, Gd(3)L has remarkable proton relaxivities at high magnetic field (r(1) = 10.2 vs 3.0 mM(-1) s(-1) for GdDOTA at 9.4 T, 37 degrees C, in H(2)O). Here we report an in vivo MRI feasibility study, complemented with dynamic gamma scintigraphic imaging and biodistribution experiments using the (153)Sm-enriched analog. MRI experiments were performed at 9.4 T in mice with Gd(3)L and the commercial contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate (GdDOTA). Gd(3)L was well tolerated by the animals at the dose of 8 micromol Gd kg(-1) body weight. Dynamic contrast enhanced (DCE) images showed considerably higher signal enhancement in the kidney medulla and cortex after Gd(3)L injection than after GdDOTA injection at an identical dose. The relaxation rates, DeltaR(1), were calculated from the IR TrueFISP data. During the excretory phase, the DeltaR(1) for various tissues was similar for Gd(3)L and GdDOTA, when the latter was injected at a three-fold higher dose (24 vs 8 micromol Gd kg(-1) body weight). These results point to an approximately three times higher in vivo relaxivity (per Gd) for Gd(3)L relative to GdDOTA, thus the ratio of the relaxivities of the two compounds determined in vitro is retained under in vivo conditions. They also indicate that the two inner sphere water molecules per Gd in Gd(3)L are not substantially replaced by endogenous anions or other donor groups under physiological conditions. Gd(3)L has a pharmacokinetics typical of small, hydrophilic complexes, involving fast renal clearance and no retention in the blood pool. The dynamic gamma scintigraphic studies and the biodistribution experiments performed in Wistar rats with (153)Sm-enriched (*)Sm(3)L are also indicative of a fast elimination via the kidneys.

Influence of molecular parameters and increasing magnetic field strength on relaxivity of gadolinium‐ and manganese‐based T1 contrast agents

“…As new T 1 agents are prepared, it would be valuable to design agents that have excellent relaxation properties over a broad range of imaging field strengths in order to take advantage of current 1.5T scanners and the increasing number of higher field scanners. This has been recognized in the recent work by Livramento et al who have described new compounds with improved r 1 at high fields (14-18). …”

Cerebrospinal and interstitial fluid transport via the glymphatic pathway modeled by optimal mass transport

“…3). The relaxivity of Gd-DTPA was assumed to be 3.1 mM −1 s −1 (De Sousa et al, 2008), TR=15ms, flip angle (theta)=15°, and tissue T1=2000ms (De Graaf et al, 2001). …”

Relaxivity of Gadolinium(III) Complexes: Theory and Mechanism

“…This transition can be used to determine the number of species present in solution [47], and, in particular, to characterize hydration equilibria for Eu(III) complexes [48][49][50][51]. Some DTTA-based chelates have been injected to mice to perform in vivo imaging experiments and showed no apparent toxicity [62,63]. Although the thermodynamic stability and kinetic inertness of bishydrated Gd(III) complexes has been often considered to be insufficient for application in human medicine, there is an intensive research to design stable chelates with two inner-sphere water molecules.…”