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

Authors

Mojmír Suchý, The University of Western Ontario
Mark Milne, The University of Western Ontario
Adam A.H. Elmehriki, The University of Western Ontario
Nevin McVicar, The University of Western Ontario
Alex X. Li, The University of Western Ontario
Robert Bartha, The University of Western Ontario
Robert H.E. Hudson, The University of Western Ontario

Document Type

Article

Publication Date

8-27-2015

Journal

Journal of Medicinal Chemistry

Volume

58

Issue

16

First Page

6516

Last Page

6532

URL with Digital Object Identifier

10.1021/acs.jmedchem.5b00621

Abstract

A series of structurally modified Tm3+ 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 Tm3+ 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. (Figure Presented).