MRI Contrast Enhancement of Necrosis by MP-2269 and Gadophrin-2 in a Rat Model of Liver Infarction

Abstract

Although both MP-2269 and gadophrin-2 feature an albumin-binding capacity, only gadophrin-2 displayed a persistent necrosis-specific contrast enhancement in the rat model of reperfused liver infarction. Therefore, the role of albumin binding in the mechanisms of NACAs should be reevaluated.

Synthesis, Characterization, and Pharmacokinetic Evaluation of a Potential MRI Contrast Agent Containing Two Paramagnetic Centers with Albumin Binding Affinity

“…The SI of the infarcted lobe after Gadophrin-2 injection increased further and persisted for up to 24 h, leading to a positive contrast between necrotic and normal liver (CR = 1.4), consistent with results of previous studies. [38,39] Despite its high albumin-binding affinity, [Gd 2 -3] does not appear to be a necrosis avid contrast reagent, supporting the suggestion that binding to albumin is probably not responsible for necrosis avidity. This is not unexpected, as albumin binding is a general feature of many drugs, including contrast agents, only a few of which have been shown to have necrosis avidity.…”

“…In vivo evaluation for liver contrast enhancement: Six normal rats and a rat with re-perfused hepatic infarction induced under laparotomy with temporary obstruction (3 h) of the blood supply to the right liver lobes [38,39] were included in MRI studies. Two reference contrast agents were commercially available; [Gd(DTPA)], and the well-known NACA bisGd-mesoporphyrin or Gadophrin-2 (supplied by the Institut für Diagnostikforschung Berlin, Germany).…”

MR Contrast Agents for Cardiac Imaging

“…Therefore the retained NACAs in necrosis are most likely removed together with necrotic materials by phagocytosis, which is supported by more recent results (Ni 2008). Questions remain as to whether the Gd-complex of NACAs is still stable after being taken up by macrophages and what the fate and consequence are of this small necrosis-binding fraction of NACAs in the human body (Ni 1998;Ni et al 2001aNi et al , 2002aNi et al , b, 2005a. These have to be further elucidated (Ni 2008).…”

“…What likely also belongs to this type is the discovery of another category of necrosis-targeting contrast agents, which represents an ongoing multiepisode story. To distinguish them from other antibody or receptor-mediated specific contrast agents with better-defined molecular targets, we proposed to nominate these newly discovered porphyrin and nonporphyrin species ''necrosis-avid contrast agents'' (NACAs) because of their remarkable affinity for necrotic and/or infarcted tissues (Ni et al 1997a(Ni et al , 2001a(Ni et al , 2005aNi 1998Ni , 2008Pislaru et al 1999;Cresens et al 2001).…”

“…By chelating a copper ion in the center of the cyclic tetrapyrrole ring, Gadophrin-3 has been introduced to improve its structural stability and safety yet still retain its targeting efficacy (Barkhausen et al 2002;Schalla et al 2004). Except for slight discoloration that faded considerably over 24 h, during animal experiments no detectable side effects have been reported with porphyrin agents at a 0.05-0.1 mmol/kg dose range (Ni et al 1994, 1997a, 1998, 2001aSchneider et al 1995Marchal et al 1996;Herijgers et al 1997;Ni 1998;Lim et al 1999;Pislaru et al 1999;Saeed et al 1999;Stillman et al 1999;Wendland et al 1999;Choi et al 2000;Marchal et al 2000;Jeong et al 2001;Saeed et al 2001). Nevertheless, despite optimistic expectations (Krombach et al 2002), further commercial development of these colored porphyrin complexes has unfortunately been abandoned by the industry (Weinmann, Schering AG, personal communication) most likely due to the predicted unsatisfactory clinical tolerance resulting from unchangeable nature of dark-colored pigments of this type of chemicals (Fig.…”