Chiral DOTA chelators as an improved platform for biomedical imaging and therapy applications

Abstract

Despite established clinical utilisation, there is an increasing need for safer, more inert gadolinium-based contrast agents, and for chelators that react rapidly with radiometals. Here we report the syntheses of a series of chiral DOTA chelators and their corresponding metal complexes and reveal properties that transcend the parent DOTA compound. We incorporated symmetrical chiral substituents around the tetraaza ring, imparting enhanced rigidity to the DOTA cavity, enabling control over the range of stereoisomers of the lanthanide complexes. The Gd chiral DOTA complexes are shown to be orders of magnitude more inert to Gd release than [GdDOTA]−. These compounds also exhibit very-fast water exchange rates in an optimal range for high field imaging. Radiolabeling studies with (Cu-64/Lu-177) also demonstrate faster labelling properties. These chiral DOTA chelators are alternative general platforms for the development of stable, high relaxivity contrast agents, and for radiometal complexes used for imaging and/or therapy.

Effect of Ligand Chirality and Hyperconjugation on the Thermodynamic Stability of a Tris(aquated) GdIII Complex: Synthesis, Characterization, and T1‐Weighted Phantom MR Image Study

“…Thus, the effect of chiral methyl pendant (L‐alanine vs. glycine) to the thermodynamic stability of the tris(aquated) Gd III complexes was realized and the effect of the chiral pendant was successfully established. Very recently, Caravan and co‐worker reported similar improvement in the stability of [Gd(DOTA)(OH 2 )] – complex by introducing chiral DOTA derivative as the ligands . Complex 1 afforded longitudinal relaxivity value of 10.95 m m –1 s –1 at 1.41 T, pH ≈ 7.4, and 25 °C.…”

Highly Stable Silver(I) Complexes with Cyclen-Based Ligands Bearing Sulfide Arms: A Step Toward Silver-111 Labeled Radiopharmaceuticals

“… 11 For such reason, BFCs must display high thermodynamic stability and kinetic inertness toward the radionuclide to prevent dissociation and competition reactions (such as transmetalation by endogenous metals or transchelation by native ligands 9 , 12 ) but also allow mild and rapid labeling conditions, especially if the carrier moiety is a thermally sensitive biomolecule. 13 Moreover, BFCs not only coordinate the metal radionuclide, but they also modulate the pharmacokinetics of the resulting molecule.…”

“…This modification was inspired by the chiral DOTA derivatives recently proposed by Dai et al which have demonstrated higher stability and faster labeling properties with copper-64 and lutetium-177 compared to the DOTA analogues. 13 …”

Chiral Separation of rac-Propylene Oxide on Penicillamine Coated Gold NPs

“…The same is true of other chiral bio-active chemicals such as agrochemicals, pesticides and flavors. In recent years, researchers have also focused on the role of chirality in other areas such as catalysis [ 1 ], chiroptical applications [ 2 , 3 ], chiral magnetism [ 4 ], chiral semiconductors [ 5 ], cellular imaging [ 6 ], sensing [ 7 ], biomedical applications [ 8 ], chiral molecular assembly on surface [ 9 ], supramolecular chirality [ 10 ] and synthesis of chiral nanoparticles (NPs) [ 11 ]. One emerging field is chiral luminescent nanomaterials which have potential applications in chiral sensing [ 7 ].…”