Gadolinium Chelates with Weak Binding to Serum Proteins

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Abstract
The authors assess the effect of weak protein binding on the efficacy of gadolinium chelates as contrast agents for magnetic resonance imaging(MRI). Chelates with no (gadopentetate dimeglumine), weak (gadobenate dimeglumine), and strong (B-21326/7) protein binding were compared by in vitro MRI at 2T (spin echo [SE]: repetition time [TR]/echo time [TE] 350/8 mseconds) on solutions in 0.5 mM bovine serum albumin and in rat whole blood, and by in vivo MRI at 2T on rat models of brain tumors (SE TR/TE 350/10 mseconds) and of focal blood-brain barrier disruption (SE TR/TE 400/15 mseconds) after injection of MPP+. Relaxation rate enhancement in the blood of normal rabbits was measured in vivo after administration of contrast agents using IR-Snapshot FLASH. Signal intensity enhancement measured in vitro for whole rat blood 0.1 mM in gadobenate was 142% relative to the same concentration of gadopentetate. Peak signal intensity enhancement in brain tumors was 87% ± 8% and 64% ± 5% after 0.1 mmol/kg intravenous administration of gadobenate and gadopentetate, respectively; in MPP+ lesions, the peak signal intensity enhancement was 22% ± 9%, 32% ± 7%, and 64% ± 14% after 0.2 mmol/kg intravenous of gadopentetate, gadobenate, and B-21326/7, respectively. In rabbits, the relaxation enhancement of blood 5 minutes after B-21326/7 and gadobenate administration was 323% and 182%, respectively, relative to the same dose (0.1 mmol/kg intravenous) of gadopentetate. Weak protein binding can substantially increase the efficacy of gadolinium chelates as general purpose contrast agents for MRI.