Synthesis and Evaluation of a High Relaxivity Manganese(II)-Based MRI Contrast Agent

Abstract

The manganese(II) ion has many favorable properties that lead to its potential use as an MRI contrast agent: high spin number, long electronic relaxation time, labile water exchange. The present work describes the design, synthesis, and evaluation of a novel Mn(II) complex (MnL1) based on EDTA and also contains a moiety that noncovalently binds the complex to serum albumin, the same moiety used in the gadolinium based contrast agent MS-325. Ultrafiltration albumin binding measurements (0.1 mM, pH 7.4, 37 degrees C) indicated that the complex binds well to plasma proteins (rabbit: 96 +/- 2% bound, human: 93 +/- 2% bound), and most likely to serum albumin (rabbit: 89 +/- 2% bound, human 98 +/- 2% bound). Observed relaxivities (+/- 5%) of the complex were measured (20 MHz, 37 degrees C, 0.1 mM, pH 7.4) in HEPES buffer (r(1) = 5.8 mM(-)(1) s(-)(1)), rabbit plasma (r(1) = 51 mM(-)(1) s(-)(1)), human plasma (r(1) = 46 mM(-)(1) s(-)(1)), 4.5% rabbit serum albumin (r(1) = 47 mM(-)(1) s(-)(1)), and 4.5% human serum albumin (r(1) = 48 mM(-)(1) s(-)(1)). The water exchange rate was near optimal for an MRI contrast agent (k(298) = 2.3 +/- 0.9 x 10(8) s(-)(1)). Variable temperature NMRD profiles indicated that the high relaxivity was due to slow tumbling of the albumin-bound complex and fast exchange of the inner sphere water. The concept of a high relaxivity Mn(II)-based contrast agent was validated by imaging at 1.5 T. In a rabbit model of carotid artery injury, MnL1 clearly delineated both arteries and veins while also distinguishing between healthy tissue and regions of vessel damage.

Hydroxy double salts intercalated with Mn(II) complexes as potential contrast agents

“…However this latter calculation might overestimate the q value, as it did not take into account the possible contribution of second sphere relaxation. ) which has q = 1 and a negligible second sphere relaxation contribution [29,30]. Taking into account the significant second-sphere contribution expected, our results for MnL 1 point to a q value between 1 and 0.…”

The extraordinary ligand binding properties of human serum albumin

“…Interestingly, the Mn(II)-EDTA-like complex bearing the same recognition synthon displays, again, a high affinity for HSA. It has been reported that in clinical concentrations, about 98% of this agent is bound to serum proteins (67).…”

Paramagnetic Phospholipid-Based Micelles Targeting VCAM-1 Receptors for MRI Visualization of Inflammation

“…The relaxivity was also measured as a function of the proton Larmor frequencies (from 0.01 to 70 MHz) and the experimental data are reported in Figure 1 (left). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 As such theories have some limitations to properly model the behaviour of slowly tumbling systems at low Larmor frequencies, 30 NMRD data were analysed only in the high-frequency region (> 5 MHz).…”