Bifunctional Chelates Optimized for Molecular MRI

Abstract

Important requirements for exogenous dyes or contrast agents in magnetic resonance imaging (MRI) include an effective concentration of paramagnetic or superparamagnetic ions at the target to be imaged. We report the concise synthesis and characterization of several new enantiopure bifunctional derivatives of (α1R,α4R,α7R,α10R)-α1,α4,α7,α10-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA) (and their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) analogues as controls) that can be covalently attached to a contrast agent delivery system using either click or peptide coupling chemistry. Gd complexes of these derivatives can be attached to delivery systems while maintaining optimal water residence time for increased molecular imaging sensitivity. Long chain biotin (LC-biotin) derivatives of the Eu(III) and Gd(III) chelates associated with avidin are used to demonstrate higher efficiencies. Variable-temperature relaxometry, 17O NMR, and nuclear magnetic resonance dispersion (NMRD) spectroscopy used on the complexes and biotin–avidin adducts measure the influence of water residence time and rotational correlation time on constrained and unconstrained systems. The Gd(III)-DOTMA derivative has a shorter water residence time than the Gd(III)-DOTA derivative. Compared to the constrained Gd(III)-DOTA derivatives, the rotationally constrained Gd(III)-DOTMA derivative has ∼40% higher relaxivity at 37 °C, which could increase its sensitivity as an MRI agent as well as reduce the dose of the targeting agent.

Differences in the Relaxometric Properties of Regioisomeric Benzyl-DOTA Bifunctional Chelators: Implications for Molecular Imaging

“…This suggests that the TSAP coordination isomer would afford a more effective contrast agent, and given the SAP/ TSAP ratios given in Figure 2, that the side isomer would be superior as a component of an MRI contrast agent. 13 However, very fast water exchange has unanticipated, and detrimental, consequences for chelate hydration which can reduce the effectiveness of the contrast agent. 17,18 Relaxometic Investigations into the Discrete Regioisomeric Chelates.…”

“…10−12 This is in turn expected to strongly influence the relaxometric properties (effectiveness as a contrast agent) of any bioconjugate derived from GdIB-DOTA. 13 The physicochemical properties of each regioisomer of GdNB-DOTA are reported. The potential for regioisomerism to influence the effectiveness of the chelate as a contrast agent in bioconjugates produced from IB-DOTA is examined with a view to determining whether regioisomerism is a consideration in the development of bioconjugates for MRI applications.…”

On Water and its Effect on the Performance of T1‐Shortening Contrast Agents

“…One significant contributor to the value of τ M in macrocyclic chelates is the coordination chemistry of the chelate. More specifically the ratio of square antiprism (SAP) to twisted square antiprism (TSAP) has been shown to play a significant role in determining relaxivity when τ R is increased ,. The addition of salts to macrocyclic chelates can alter the SAP/TSAP ratio.…”

Recent Advances in Bifunctional Paramagnetic Chelates for MRI

“…to prepare multimeric MR‐optical CAs for multimodal imaging and prostate‐specific membrane antigen (PSMA)‐targeted CAs, or for conjugation to peptide‐ampiphiles nanofibers for reporting on biomaterial localization in vivo and as alternative linking mode to oligonucleotide‐tailored AuNPs for reporting gene detection by MRI . Structural variations on BFCAs for click‐based reaction include DOTA analogues with propargyl groups on the macrocyclic backbone such as 38 or 39 , formally derived from DOTMA by introduction of a reactive azide on one of the propionic side arms …”