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

Abstract

The use of lanthanide-based contrast agents for magnetic resonance imaging (MRI) has become an integral component of this important diagnostic modality. These inert chelates typically possess high thermodynamic stability constants that serve as a predictor for in vivo stability and low toxicity. Recently a new class of contrast agents was reported having a significantly lower degree thermodynamic stability while exhibiting biodistribution profiles indicative of high stability under biological conditions. These observations are suggestive that the nature of contrast agent stability is also dependent upon the kinetics of complex dissociation; a feature of potential importance when contemplating the design of new chelates for in vivo use. In this paper we present a study of the kinetics of acid catalyzed dissociation, thermodynamic stability, serum stability and biodistribution of a series of DOTA-tetraamide complexes that have been substituted with peripheral hydroxyl groups. The data indicate that these non-traditional contrast agents exhibit in vivo stability comparable to agents with much higher log K ML values demonstrating the important contribution of kinetic inertness.

Stability and Toxicity of Contrast Agents

“…Interestingly, another closely related positively charged complex, Lu(DOTAM-12OH) 3+ (Chart 4.6) did not exhibit any acute toxicity when administered at a typical MRI dose. The exact reason for this observation is not been established but it is likely that the decreased toxicity is the consequence of the presence of the 12 peripheral alcohol OH groups, which somehow mask the positive charge on the complex [252,253].…”

Investigations into whole water, prototropic and amide proton exchange in lanthanide(iii) DOTA-tetraamide chelates

“…These chelates were engineered in our lab along with a third, 3 , as part of a program to investigate improving the in vivo tolerance of such chelates. 23,24 It should be noted that all three chelates were found to adopt the SAP isomer exclusively and all three exhibited CEST properties typical of that coordination geometry (supplementary information). The CEST properties of Eu 1 and Eu 2 were almost identical and fitting of the CEST data afforded similar overall exchange rates, k ex obs , which accelerate with increasing pH in a comparable manner to EuDOTAM (Fig.…”

Magnetic resonance tumor targeting imaging using gadolinium labeled human telomerase reverse transcriptase antisense probes

“…The conjunction rate of Gd-DOTA-ASON was much improved compared with a report by Bartlett et al (24) Although detailed reasons are yet to be clarified, these results are partially attributed to higher pH and longer reaction time, which facilitate the chelating process. (24,25,31) MRI is an advanced and preferred imaging modality in the diagnosis of a wide range of malignancies, particularly when supplemented with Gd-DTPA dynamic contrast enhancement (DCE). (32,33) Nevertheless, use of MRI DCE as an extracellular contrast agent depends largely on the tumor blood supply, and the acquisition process is limited by time.…”

“…The verification of DOTA-ASON/SON conjunction was performed following the procedure described by Derek W. Bartlett et al (24,25) In brief, equimolar amounts of Gd chloride (GdCl 3 ) and either DOTA-ASON/SON or DOTA were added into a microcentrifuge tube and mixed with 0.2 M PBS (pH 7.5). The microcentrifuge tubes were incubated for 45 min at 60°C for the labeling reaction.…”