Manganese: a new contrast agent for lung imaging? Oliviero L. Gobbo a *, Magdalena Zurek b , Frederic Tewes a , Carsten Ehrhardt a and Yannick Crémillieux b * Lung parenchyma remains one of the most difficult tissues to be imaged by means of magnetic resonance imaging (MRI). Several MRI techniques are routinely used for lung imaging. However, manganese-enhancement MRI (MEMRI) technique has not been associated with pulmonary MRI. Here, we evaluated T 1 -enhancement in the rat lung after a manganese instillation, using a 4.7 T magnet with a radial ultrashort echo time sequence. Our data showed that the signal intensity was increased in lungs receiving a manganese solution compared with a control solution to the lungs. MR signal enhancements above 30% were measured in lung parenchyma following 200 ml instillation of a1mM manganese chloride solution. MEMRI, therefore, may be a useful novel tool for enhancing signal intensity and image contrast in lung tissue. Copyright © 2012 John Wiley & Sons, Ltd. Keywords: MEMRI; lung imaging; manganese; aerosol contrast agent; UTE lung MRI 1. INTRODUCTION Magnetic resonance imaging (MRI) is a well-established tool for investigating many organs. The lungs, however, are the most challenging to image. Susceptibility effects induced by multiple air and tissue interfaces, cardiac and respiratory movements and low-water density, translate into weak MRI signals in the lung (1,2). Several techniques have improved lung MRI, e.g. by the use of hyperpolarized (HP) contrast media like HP helium-3 (3,4) and xenon-129 (5) or by means of pulse sequences with short echo time [ultrashort echo time sequence (UTE)-MRI] (6). Additionally it has been shown that contrast agents such as gadolinium chelates can be used for enhancing the contrast and improving the anatomic resolution of pulmonary imaging (7,8); however, their use as aerosols for MR ventilation imaging was shown to be potentially compromised by their high viscosity (9). Manganese ion (Mn 2+ ) represents another T 1 -shortening con- trast agent applied in vivo. The manganese-enhancement MRI (MEMRI) technique has been used particularly in neuroscience (10–13), where transport of manganese cations along axons and across synapses can be used to visualize neuronal tract and neuronal activation. Compared with gadolinium chelates, Mn 2+ is characterized by a small hydrodynamic diameter and high water solubility, making it attractive for aerosolized administration to the lungs. Even though manganese is required for cellular homeo- stasis, toxicity can occur, with chronic exposure to neurons, lungs, heart and liver being noted. However, there are no known reports of Mn toxicity following a single administration. Rather, Mn toxicity is more frequently associated with overexposure to the metal, which can lead to Mn accumulation, particularly in brain regions, including the basal ganglia structures (14). In other words, the main health concern associated with the use of manganese is that chronic exposure to excessive levels of this metal (>100 mM in primary astrocyte culture) results in neurodegenerative damage (called manganism) resembling Parkinson’ s disease (15). Its neurotoxicity seems to be due to an excessive accumulation in astrocytes, which compromises energy metabolism and impairs astrocytic–neuronal communication (16). After the brain, the second major target organ for Mn toxicity is the heart. Indeed, manganese is known to block normal calcium fluxes in the heart, causing prominent cardiotoxicity (17). However by using Mn com- plexes (18) or a low concentation of manganese, the feasibility of valuable and relevant pre-clinical MEMRI investigations with limited pathological impact on imaged animals has been demonstrated. With regard to lung imaging, MEMRI has previously been used for the detection of a particular type of lung cancer called malignant mesothelioma (MM). Early diagnosis of MM is critical for a better prognosis, but this is often difficult because of the lack of disease- specific diagnostic imaging (19). To detect this tumor in the lungs, Hasegawa et al. (19) administered manganese intravenously and monitored the specific accumulation of Mn 2+ in MM cells. Indeed, they found that these cells accumulate more manganese than human mesothelial cells, owing to an overexpressed manganese-superoxide dismutase (Mn-SOD) protein. The aim of this proof-of-concept study was to evaluate the utility and relevance of manganese, as an instilled contrast agent, for MR lung imaging in small animal. 2. EXPERIMENTAL SECTION 2.1. Animals The experiments were carried out using male Sprague–Dawley rats supplied by Charles River Laboratory (L’ Arbresle, France) * Correspondence to: Yannick Crémillieux, Centre de Recherche Cardio-Thoracique, Université Bordeaux 2, 146 rue Léo-Saignat, 33076 Bordeaux, France. E-mail: yannick.cremillieux@u-bordeaux2.fr Oliviero L. Gobbo, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin D2, Ireland. E-mail: ogobbo@tcd.ie a O. L. Gobbo, F. Tewes, C. Ehrhardt School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland b M. Zurek, Y. Crémillieux Creatis-LRMN, Université de Lyon I, Villeurbanne, France Short Communication Received: 6 October 2011, Revised: 7 June 2012, Accepted: 14 June 2012, Published online in Wiley Online Library: 2012 (wileyonlinelibrary.com) DOI: 10.1002/cmmi.1483 Contrast Media Mol. Imaging 2012, 7 542–546 Copyright © 2012 John Wiley & Sons, Ltd. 542