Improved Evaluation of Myocardial Perfusion and Viability With the Magnetic Resonance Blood Pool Contrast Agent P792 in a Nonreperfused Porcine Infarction Model

Objectives-Recent advances in the design of MRI contrast agents have rendered the lanthanide complexes of DOTA-tetraamide ligands of considerable interest, both as responsive MR agents and paramagnetic chemical exchange saturation transfer agents. The potential utility of these complexes for in vivo applications is contingent upon them being well tolerated by the body. The purpose of this study was to examine how the nature of the amide substituent, and in particular its charge, affected the fate of these chelates postinjection.Materials and Methods-Complexes of 6 DOTA-tetraamide ligands were prepared in which the nature of the amide substituent was systematically altered. The 6 ligands formed 3 series: a phosphonate series that included tri-cationic, mono-anionic, and polyanionic complexes; a carboxylate series made up of a tri-cationic complex and a mono-anionic complex; and lastly, a tricationic complex with an aromatic amide substituent. These complexes were labeled with an appropriate radioisotope, either 153 Gd or 177 Lu, and the biodistribution profiles in rats recorded 2 hours postinjection.Results-Biodistribution profiles were initially acquired at low doses to minimize adverse effects. All the complexes studied were found to be excreted primarily through the renal system, with the majority of the dose being found in the urine. None of the complexes exhibited substantial uptake by bone, liver, and spleen, except for a complex with 4 phosphonate groups that exhibited significant bone targeting capabilities. Increasing the dose of each complex to that of a typical MR contrast agent Reprints NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript was found to render all 3 tri-cationic complexes studied here acutely toxic. In contrast, no ill effects were observed after administration of similar doses of the corresponding anionic complexes.Conclusions-The absence of uptake by the liver and spleen indicate that irrespective of the ligand structure and charge, these complexes are not prone to dissociation in vivo. This is in agreement with previously published work that indicates high kinetic inertness for this class of compounds. At low doses, all complexes were well tolerated; however, for applications that require higher doses, the structure and charge of the ligand becomes a fundamentally important parameter. The results reported herein demonstrate the importance of incorporating negatively charged groups on amide substituents if a DOTA-tetraamide complex is to be employed at high doses in vivo. KeywordsLanthanide complexes; Biodistribution; MRI contrast agents; PARACEST agentsComplexes of Gd 3+ have found widespread application as contrast agents in magnetic resonance imaging (MRI) 1,2 in which they are administered in relatively high doses, typically 0.1-0.5 mmol kg −1 . Numerous Gd 3+ complexes have been approved for clinical use and, without exception, the ligand systems employed are octadentate polyamino-polycarboxylates that render the resulting complex either neutral or ...

Section: Discussionmentioning

confidence: 51%

The Effect of the Amide Substituent on the Biodistribution and Tolerance of Lanthanide(III) DOTA-Tetraamide Derivatives

Woods¹,

Caravan

Geraldes

et al. 2008

“…Several studies showed that perfusion defects and viability in acute myocardial infarction can be reliably assessed after administration of intravascular contrast agents. [27][28][29] However, in the setting of chronic myocardial infarction most of the studies with contrastenhanced MRI were performed with extracellular contrast agents, and most among those with gadopentetate dimeglumine. Extracellular contrast materials with the potential to decrease T1 values to a greater extent compared with Gd-DTPA offer the possibility to improve the delineation of infarcted myocardium.…”

Section: Discussionmentioning

confidence: 99%

Low Dose Gadobenate Dimeglumine for Imaging Of Chronic Myocardial Infarction in Comparison With Standard Dose Gadopentetate Dimeglumine

Bauner

Reiser

Huber

2009

“…[1][2][3] Recent technical advances in myocardial perfusion imaging with magnetic resonance imaging (MRI), such as the use of parallel imaging 4 and intravascular contrast agents, 5 and the development of novel approaches with blood oxygen-level dependent contrast 5 seem bound to turn MRI into an increasingly useful tool for the diagnoses of coronary artery disease. There is compelling evidence that any impairment of the coronary hyperemic response does not simply reflect the presence and severity of any up-stream coronary lesions, but is a sensitive marker of coronary vasoreactivity.…”

mentioning

confidence: 99%

Variability of Myocardial Blood Flow Measurements by Magnetic Resonance Imaging in the Multi-Ethnic Study of Atherosclerosis

Jerosch‐Herold¹,

Vázquez²,

Wang³

et al. 2008