ParaCEST MRI contrast agents capable of derivatizationvia “click” chemistry

Abstract

A comprehensive series of lanthanide chelates has been prepared with a tetrapropargyl DOTAM type ligand. The complexes have been characterized by a combination of (1)H NMR, single-crystal X-ray crystallography, CEST and relaxation studies and have also been evaluated for potential use as paramagnetic chemical exchange saturation transfer (ParaCEST) contrast agents in magnetic resonance imaging (MRI). We demonstrate the functionalization of several chelates by means of alkyne-azide "click" chemistry in which a glucosyl azide is used to produce a tetra-substituted carbohydrate-decorated lanthanide complex. The carbohydrate periphery of the chelates has a potent influence on the CEST properties as described herein.

The btp [2,6-bis(1,2,3-triazol-4-yl)pyridine] binding motif: a new versatile terdentate ligand for supramolecular and coordination chemistry

“…The majority of reported uses of the CuAAC reaction have not taken advantage of the coordinative abilities of the 1,2,3-triazole motif, rather employing it as a linker between other functional building blocks, such as their use in coupling Ln(III) cyclen complexes to redox-active motifs, 73 carbohydrate building blocks 74 or another Ln(III) cyclen complex 75 an area of research developed by Faulkner et al, Hudson and co-workers and our own research group, respectively, for application in sensing and imaging. The CuAAC reaction has also been used to 'click' modifications onto the 4-pyridyl position of terdentate ligands, such as dpa derivatives in order to synthesise metal chelators, 76 form Ln(III) luminescent probes, 77 and graft these onto silica nanoparticles.…”

Enhancing magnetic resonance imaging with contrast agents for ultra-high field strengths

“…94 Hudson and co-workers synthesized a series of PARACEST agents 84 – 87 to study the CEST effect. 95,96 The CEST effects of complexes 84 – 86 were greater than 18%, whereas the analogous Tm III - and Dy III -containing complexes produced CEST effects less than 18%. 95 Complex 87 also has been studied for its pH responsive CEST effect.…”

“…95,96 The CEST effects of complexes 84 – 86 were greater than 18%, whereas the analogous Tm III - and Dy III -containing complexes produced CEST effects less than 18%. 95 Complex 87 also has been studied for its pH responsive CEST effect. 96 This complex produced a six-fold increase in CEST effect upon changing pH from 6.5 to 7.0 (9.4 T and 37 °C).…”

Synthesis of 1,4,7,10‐Tetra‐azacyclododecan‐1,4,7,10‐tetra‐azidoethylacetic Acid (DOTAZA) and Related “Clickable” DOTA Derivatives

“…[25] Again, this route was efficient, easily scalable, and started from malic acid (18), which was a cheap enantiomerically pure precursor. We prepared methyl ester 22 and both enantiomers of benzyl ester 23 to allow flexibility in terms of the conditions required for deprotection of the esters in the target DOTAZA derivatives and to gain access to stereoisomeric DOTAZA derivatives.…”

“…Derivatives 5, which have fourfold symmetry, allow the conjugation of four targeting vectors or other effectors and, thus, are attractive for the assembly of multivalent imaging reagents [17] or tailored MRI agents. [18] Compounds of type 6 are tunable analogues of DOTA À tris(-tert-butyl)ester 1. They allow the conjugation of a targeting vector to the free carboxylic acid and three effectors through click chemistry for tuning their pharmacokinetic properties or the introduction of additional imaging or therapeutic agents (dual-or multi-modal imaging agents).…”