11 research outputs found
MRI Responsive Contrast Agents: Towards Sensing and Imaging of Neurotransmitters
Amino acid neurotransmitters are considered as key biological messengers. Thus, their quantification and monitoring would allow a greater understanding of the molecular mechanisms associated with the function of the brain and the associated neurological disorders. Currently no method exists that can non-invasively determine the concentration of neurotransmitters in vivo. Magnetic resonance imaging (MRI) has recently been demonstrated as a promising method to monitor physiological events noninvasively, with high temporal and spatial resolution. Here, we address the issue of neurotransmitter monitoring through MRI by describing our progress towards the development of MR probes for tracking the change in neurotransmitter concentrations within the brain. We designed and synthesized two âturn-offâ DO2A derived gadolinium based probes, which respond to changes in neurotransmitters concentrations at physiological pH. These complexes consist of a dual receptors, which on interaction with the neurotransmitters modulate their relaxivity. In vitro inversion recovery measurements were performed at physiological pH and at 60 MHz to monitor the changes in relaxivity upon the addition of neurotransmitters. Both GdL1 and GdL2 complexes showed a relaxivity change of up to 75% upon the addition of millimolar concentrations of certain neurotransmitters. Luminescence studies were also performed with EuL1 and EuL2 in the absence and presence of the same neurotransmitters. Changes in the europium emission spectra and a modulation of the hydration number (q) were observed upon addition of neurotransmitters for EuL1. The observed decrease in q was in good agreement with the change in relaxivity. These preliminary results give valuable insights into understanding the structural aspects of the contrast agent interaction with neurotransmitters and will help to improve the molecular design of new responsive agents. The financial support of the Max-Planck Society and the CNRS is gratefully acknowledged
MRI sensing of neurotransmitters with a crown-ether appended Gd3+ complex
Molecular MRI approaches that detect biomarkers associated to neural activity would allow more direct observation of brain function than current functional MRI based on blood-oxygen-level-dependent contrast. Our objective was to create a synthetic molecular platform with appropriate recognition moieties for zwitterionic neurotransmitters that generate an MR signal change upon neurotransmitter binding. The gadolinium complex (GdL) we report offers ditopic binding for zwitterionic amino acid neurotransmitters, via: i) interactions between the positively charged and coordinatively unsaturated metal centre and the carboxylate function and ii) between a triazacrown ether and the amine group of the neurotransmitters. GdL discriminates zwitterionic neurotransmitters from monoamines. Neurotransmitter binding leads to a remarkable relaxivity change, related to a decrease in hydration number. GdL was successfully used to monitor neural activity in ex vivo mouse brain slices by MRI
Macrocyclic Gd(3+) complexes with pendant crown ethers designed for binding zwitterionic neurotransmitters
A series of Gd3+ complexes exhibiting a relaxometric response to zwitterionic amino acid neurotransmitters was synthesized. The design concept involves ditopic interactions 1)â
between a positively charged and coordinatively unsaturated Gd3+ chelate and the carboxylate group of the neurotransmitters and 2)â
between an azacrown ether appended to the chelate and the amino group of the neurotransmitters. The chelates differ in the nature and length of the linker connecting the cyclen-type macrocycle that binds the Ln3+ ion and the crown ether. The complexes are monohydrated, but they exhibit high proton relaxivities (up to 7.7â
mMâ1âsâ1 at 60â
MHz, 310â
K) due to slow molecular tumbling. The formation of ternary complexes with neurotransmitters was monitored by 1H relaxometric titrations of the Gd3+ complexes and by luminescence measurements on the Eu3+ and Tb3+ analogues at pHâ
7.4. The remarkable relaxivity decrease (â80â) observed on neurotransmitter binding is related to the decrease in the hydration number, as evidenced by luminescence lifetime measurements on the Eu3+ complexes. These complexes show affinity for amino acid neurotransmitters in the millimolar range, which can be suited to imaging concentrations of synaptically released neurotransmitters. They display good selectivity over non-amino acid neurotransmitters (acetylcholine, serotonin, and noradrenaline) and hydrogenphosphate, but selectivity over hydrogencarbonate was not achieved
Toward MRI and Optical Detection of Zwitterionic Neurotransmitters: Near-Infrared Luminescent and Magnetic Properties of Macrocyclic Lanthanide(III) Complexes Appended with a Crown Ether and a Benzophenone Chromophore
Thanks to their versatile magnetic and luminescence features, lanthanide complexes have gained a central position in biomedical imaging as magnetic resonance imaging (MRI) contrast agents and optical imaging probes. In addition, appropriate chemical design allows modification of the magnetic relaxation properties of GdIII complexes and the optical properties of visible- or near-infrared (NIR)-emitting lanthanide chelates upon interaction with various biomarkers, which makes them ideal candidates for the creation of responsive agents. In this Forum Article, we demonstrate such design principles as well as the difficulties encountered in the context of neurotransmitter (NT) detection. Lanthanide(III) complexes of a macrocyclic ligand incorporating a benzophenone chromophore and a monoazacrown ether (LnL3) have been synthesized as responsive probes to monitor amino acid NTs either in MRI (Ln = Gd) or in NIR optical detection (Ln = Nd or Yb). The parameters characterizing the water exchange and rotational dynamics of the gadolinium(III) complex were assessed by 17O NMR and 1H NMRD. In the presence of zwitterionic NTs, the inner-sphere water molecule is replaced by the carboxylate function of the NTs in the gadolinium(III) complex, leading to a decrease of the longitudinal relaxivity from 6.7 to 2â2.5 mMâ1 sâ1 (300 MHz and 37 °C). The apparent affinity constants range from Ka = 35 for Îł-aminobutyric acid (GABA) to 80 Mâ1 for glycine and glutamate, and there is no selectivity with respect to hydrogen carbonate (Ka = 232; pH 7.4). The gadolinium(III) complex interacts with human serum albumin (HSA), resulting in a 60% increase in the relaxivity (20 MHz, 37 °C) in the absence of NTs. The HSA-bound complex, however, was revealed to be less responsive to NTs because of displacement of the GdIII-bound water by HSA, which was confirmed by the hydration number calculated from luminescence lifetimes of the HSA-bound europium(III) complex. The creation of an imaging agent suitable for NIR detection of NTs for an enhanced sensitivity in biological systems using the benzophenone (BP) moiety as the sensitizer of lanthanide luminescence was also attempted. Upon excitation at 300 nm of the BP chromophore in aqueous solutions of NdL3 and YbL3, characteristic NIR emissions of NdIII and YbIII were observed because of 4F3/2 â 4IJ (J = 9/2â13/2) and 2F5/2 â 2F7/2 transitions, respectively, indicating that this chromophore is a suitable antenna. Despite these promising results, luminescence titrations of NdIII and YbIII complexes with NTs were not conclusive because of chemical conversion of the ligand triggered by light, preventing quantitative analysis. The observed photochemical reaction of the ligand is strongly dependent on the nature of the lanthanide chelated; it is considerably slowed down in the presence of NdIII and EuIII