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

Abstract

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 ...

Synthesis and evaluation of lanthanide ion DOTA–tetraamide complexes bearing peripheral hydroxyl groups

“…complexes of LuL 1 , LuL 4 and LuL 8 (total [Lu 3+ ]: 0.1 mmolkg −1 ) showed signs of distress immediately post-injection and expired within 5 minutes. Given the slow rate of complex dissociation established both in vitro and in serum, death occurs too rapidly to be the result of dissociation of the complex and must be the result of an inherent toxicity of these tri-cationic complexes, consistent with our earlier report [8]. The cause of death was previously postulated to involve an interaction between the complex and heart tissue that caused a rapid weakening of the heart beat [8].…”

“…Such high doses can overwhelm transport pathways in the body, significantly altering the biodistribution profiles [21]. It has recently been reported that some tri-cationic DOTA-tetraamide complexes are acutely toxic in rodents at these high dose levels [8]. In order to assess the effect of this increased dose, injections of all five chelates were formulated with carrier added.…”

“…In addition, the amide substituent may be modified in such a way that further fine tuning of water exchange kinetics is possible [4]. These changes in the nature of coordinate bonding with the metal ion have been found to exert an important influence over the kinetics of dissociation [5], thermodynamic stability [5–7] and physiological tolerance [8]. Our interest in CEST imaging using PARACEST agents has prompted an effort to refine this class of chelate with a view to in vivo applications.…”

The effect of regioisomerism on the coordination chemistry and CEST properties of lanthanide(III) NB-DOTA-tetraamide chelates

“…Ideally the agent would adopt exclusively the conformation of the SAP isomer observed for S - SSSS -Eu 2 3+ . The chelates would need to be rendered both nontoxic (as these tricationic chelates are almost not well tolerated in vivo) [52] and made water-soluble; both of these prerequisites could be achieved through incorporation of three or four anionic groups, such as carboxylates, into the chelate structure [52]. …”

The Developmental History of the Gadolinium Chelates as Intravenous Contrast Media for Magnetic Resonance

“…In the past 5 years (2007-2011), there have been 92 publications (of 552 or 17%) in Investigative Radiology that involved in a principal manner the gadolinium chelates. This included both basic research and clinical papers investigating new agents, [75][76][77][78][79][80][81][82][83][84][85][86][87][88] expanding the clinical applications for commonly used agents, 38,89 -123 assessing new imaging techniques, 124 -135 and evaluating the physicochemical properties and safety of these agents, 136 -148 focusing in particular on NSF. 46,73,74,149 -162 On the basis of target-specificity and clinical application of gadolinium agents, hepatobiliary contrast agents (Gd-BOPTA and Gd-EOB-DTPA) 89,92-96,98 -100,103-105,111,112,114,115,117-119,139 and blood pool agents (MS-325) 91,102,108 -110,116,121,123 constituted the emphasis of research involving MR contrast agents.…”