Original Research ARTICLE
In-depth study of a novel class of ditopic gadolinium(III)-based MRI probes sensitive to zwitterionic neurotransmitters
- 1MR Neuroimaging Agents, Max Planck Institute for Biological Cybernetics, Germany
- 2Center for Advanced Scientific Research, Faculty of Science, University of A Coruña, Spain
The efficacy of Gd-based low-molecular weight ditopic MRI probes on binding zwitterionic neurotransmitters (ZNTs) relies on their structural compatibility. ZNTs are challenging biomarkers for monitoring chemical neurotransmission due to their intrinsic complexity as target molecules. In this work, we focus on tuning the cyclen- and azacrown-based binding sites properties to increase the affinity towards ZNTs. Our approach consisted in performing structural modifications on the binding sites in terms of charge and size, followed by the affinity evaluation through T1-weighted relaxometric titrations. We prepared and investigated six Gd3+ complexes with different structures and thus properties, which were found to be acetylcholine insensitive; moreover, two of them displayed considerably stronger affinity towards glutamate and glycine over hydrogencarbonate and other ZNTs. Complexes with small and non-charged or no substituents on the azacrown moiety displayed the highest affinities towards ZNTs, followed by strong decrease in longitudinal relaxivity r1 of around 70 %. In contrast, hosts with negatively charged substituents exhibited lower decrease in r1 of nearly 30 %. The thorough investigations involving relaxometric titrations, luminescence and NMR diffusion experiments, as well as theoretical density functional theory calculations, revealed that the affinity of reported hosts towards ZNTs is greatly affected by the remote pendant on the azacrown derivative.
Keywords: Crown Ethers, Gadolinium, Magnetic Resonance Imaging, neurotransmitters, Zwitter ion
Received: 27 Mar 2019;
Accepted: 25 Jun 2019.
Edited by:Wen-Sheng Chung, National Chiao Tung University, Taiwan
Reviewed by:Apurba L. Koner, Indian Institute of Science Education and Research, Bhopal, India
Ken C. Leung, Hong Kong Baptist University, Hong Kong
Copyright: © 2019 Toljić, Platas-Iglesias and Angelovski. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Mx. Goran Angelovski, Max Planck Institute for Biological Cybernetics, MR Neuroimaging Agents, Tübingen, Germany, firstname.lastname@example.org