Mn-citrate and Mn-HIDA: intermediate-affinity chelates for manganese-enhanced MRI.

In this study we investigated two manganese chelates in order to improve the image enhancement of manganese-enhanced MRI and decrease the toxicity of free manganese ions. Since both MnCl2 and a low-affinity chelate were associated with a slow continuous decrease of cardiac functions, we investigated intermediate-affinity chelates: manganese N-(2-hydroxyethyl)iminodiacetic acid (Mn-HIDA) and Mn-citrate. The T-1 relaxivity values for Mn-citrate (4.4 mM(-1) s(-1)) and Mn-HIDA (3.3 mM(-1) s(-1)) in artificial cerebrospinal fluid (CSF) were almost constant in a concentration range from 0.5 to 5 mM at 37 degrees C and 4.7 T. In human plasma, the relaxivity values increased when the concentrations of these Mn chelates were decreased, suggesting the presence of free Mn2+ bound with serum albumin. Mn-HIDA and Mn-citrate demonstrated a tendency for better contractility when employed with an isolated perfused frog heart, compared with MnCl2. Only minimal changes were demonstrated after a venous infusion of 100 mM Mn-citrate or Mn-HIDA (8.3 mu mol kg(-1) min(-1)) in rats and a constant heart rate, arterial pressure and sympathetic nerve activity were maintained, even after breaking the blood-brain barrier (BBB). Mn-citrate and Mn-HIDA could not cross the intact BBB and appeared in the CSF, and then diffused into the brain parenchyma through the ependymal layer. The responses in the supraoptic nucleus induced by the hypertonic stimulation were detectable. Therefore, Mn-citrate and Mn-HIDA appear to be better choices for maintaining the vital conditions of experimental animals, and they may improve the reproducibility of manganese-enhanced MRI of the small nuclei in the hypothalamus and thalamus. Copyright (C) 2012 John Wiley & Sons, Ltd.