Mark Milne

Maximizing T2‐exchange in Dy3+DOTA‐(amide)X chelates: Fine‐tuning the water molecule exchange rate for enhanced T2 contrast in MRI

The water molecule exchange rates in a series of DyDOTA‐(amide)X chelates were fine‐tuned to maximize the effects of T2‐exchange line broadening and improve T2 contrast.

A DOTAM-based paraCEST agent favoring TSAP geometry for enhanced amide proton chemical shift dispersion and temperature sensitivity.

The Tm(3+) chelate of DOTAM [1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane] possessing sterically demanding t-butyl amide substitution favors TSAP geometry. This chelate displayed a paraCEST signal associated with the highly shifted amide proton signal at approximately -100 ppm that was beyond the frequency of macromolecule magnetization transfer. This signal also displayed high temperature dependence (0.57 ppm °C(-1)) in the range of 35-42 °C and at neutral pH.

DOTAM-type ligands possessing arginine pendant groups for use in PARACEST MRI.

A synthetic methodology was developed for the preparation of metal-chelating ligands that possess arginine pendant groups relying on the alkylation of 1,4,7,10-tetraazacyclododecane (cyclen) with arginine-containing electrophiles. Conditions for the selective trialkylation or peralkylation of cyclen are described, the outcome being dependent on the nature of the arginine-derived electrophile and the solvent used for the reaction. Lanthanide metal complexes of the ligands prepared by the described route were evaluated for their suitability as PARACEST contrast agents for use in magnetic resonance imaging. The Dy(3+) and Tm(3+) complexes display CEST effects that are associated with the amide protons proximate to the metal center. These signals exhibit pH dependence in the range of 6.0-8.0 and thus may have the potential for pH measurement in physiological range.

Water-soluble gold nanoparticles (AuNP) functionalized with a gadolinium(III) chelate via Michael addition for use as a MRI contrast agent

A contrast agent suitable for magnetic resonance imaging based on small, water soluble gold nanoparticles (AuNP) conjugated to over 50 Gd3+ chelators has been prepared by using an interfacial Michael addition in aqueous media. The resultant chelator-AuNP conjugates have been successfully characterised by 1H NMR spectroscopy, IR spectroscopy, ICP-OES, ζ-potential analysis, TEM and MRI. T1-weighted in vivo images of mouse kidney were obtained using the agent at 9.4 T. A preliminary in vivo experiment produced no ill effects and the clearance profile of the agent suggests it is suitable for animal testing at clinically relevant concentrations.

Introduction of Peripheral Carboxylates to Decrease the Charge on Tm3+ DOTAM-Alkyl Complexes: Implications for Detection Sensitivity and in Vivo Toxicity of PARACEST MRI Contrast Agents

A series of structurally modified Tm(3+) DOTAM-alkyl complexes as potential PARACEST MRI contrast agents has been synthesized with the aim to decrease the overall positive charge associated with these molecules and increase their biocompatibility. Two types of structural modification have been performed, an introduction of terminal carboxylate arms to the alkyl side chains and a conjugation of one of the alkyl side chains with aspartic acid. Detailed evaluation of the magnetic resonance imaging chemical exchange contrast associated with the structurally modified contrast agents has been performed. In contrast to the acutely toxic Tm(3+) DOTAM-alkyl complexes, the structurally modified compounds were found to be tolerated well during in vivo MRI studies in mice; however, only the aspartic acid modified chelates produced an amide proton-based PARACEST signal.

Synthesis of a poly(Gd(III)-DOTA)–PNA conjugate as a potential MRI contrast agent via post-synthetic click chemistry functionalization

Herein we present a method for the simultaneous, multiple conjugation of alkynyl-(Gd(III)-DOTA) moieties to a PNA oligomer possessing a domain of azide residues. This is achieved in a single Huisgen type copper-catalyzed azide alkyne cycloaddition (CuAAC) reaction after the oligomer assembly is completed. A triplex formed between the labelled PNA and riboadenylic acid, [(Gd(III)-DOTA)4–PNA]2:poly(rA), displayed higher relaxivities at any field strength compared to the single-stranded probe at the same concentration of Gd3+ ions as determined by nuclear magnetic resonance dispersion (NMRD) studies.

DOTMA-based amides (DOTMAMs) as a platform for the development of PARACEST MRI contrast agents

A synthetic methodology leading to previously unknown DOTMA-based secondary amides (DOTMAMs) has been developed. Alkylation of cyclen with L-lactic acid-derived pseudohalides was used as a key step affording the alkyl- and aryl-decorated DOTMAMs. Amino acid-decorated DOTMAMs were obtained via peptide coupling between DOTMA and protected amino acids. Metallation of the DOTMAMs ligand with Tm3+ gave complexes exhibiting proximal amide proton based paramagnetic CEST effects at <−50 ppm relative to water.