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

Abstract

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 (LnL 3 ) 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 2–2.5 mM–1 s–1 (300 MHz and 37 °C). The apparent affinity constants range from K a = 35 for γ-aminobutyric acid (GABA) to 80 M–1 for glycine and glutamate, and there is no selectivity with respect to hydrogen carbonate (K a = 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 NdL 3 and YbL 3 , characteristic NIR emissions of NdIII and YbIII were observed because of 4F3/2 → 4I J (J = 9/2–13/2) and 2F5/2 → 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.

Investigations into the effects of linker length elongation on the behaviour of calcium-responsive MRI probes

“…Our results also support the coordination of the amide group both in the absence and in the presence of Ca 2+ , in line with the hydration numbers determined from luminescence lifetime measurements, which point to monohydrated complexes after Ca 2+ binding. This was also supported in a number of previous studies by 17 O NMR measurements, [32][33][34] which provided hyperfine coupling constants A/ħ that confirmed the formation of mono-hydrated species. The higher relaxivities observed for the Ca 2+ -bound form of GdL 2 compared to GdL 1 are therefore not likely related by an increased number of coordinated water molecules, but perhaps to a more important contribution of second-sphere water molecules.…”

Metal-based imaging agents: progress towards interrogating neurodegenerative disease

“…More recently, Toth and co-workers extended this design strategy by attaching a benzophenone chromophore to the lanthanide ligand site. 49 Incorporation of this flat aromatic substituent led to an increased interaction with albumin causing an enhancement in the overall relaxivity. Unfortunately, this came with an overall decrease in the neurotransmitter response.…”

Isocyanate Insertion into a La–P Phosphide Bond: A Versatile Route to Phosphaureate-Bridged Heterobimetallic Lanthanide–Coinage-Metal Complexes

“…The chemistry of the lanthanides (Ln) has advanced to be a very important field of research in modern inorganic chemistry. 1 , 2 As lanthanides are well-known for their magnetic and luminescent properties, the applications of lanthanide-containing molecules range from molecular magnetism 3 − 11 and (bio)analytical sensors 12 − 14 to optical communication 15 and modern catalysis. 16 − 31 In recent years, new strategies to systematically analyze and design lanthanide complexes with the desired chemical, magnetic, or photophysical properties have emerged.…”

“…The chemistry of the lanthanides (Ln) has advanced to be a very important field of research in modern inorganic chemistry. , As lanthanides are well-known for their magnetic and luminescent properties, the applications of lanthanide-containing molecules range from molecular magnetism − and (bio)­analytical sensors − to optical communication and modern catalysis. − In recent years, new strategies to systematically analyze and design lanthanide complexes with the desired chemical, magnetic, or photophysical properties have emerged. ,,− In this context, transition metals such as iron­(0/II/III), − nickel­(II), − and zinc­(II) ,, have been used to influence the magnetic behavior of lanthanide compounds, whereas e.g. iridium­(III), rhenium­(I), platinum­(II), − palladium­(II), zinc­(II), , gold­(I), ,, and silver­(I) have been introduced for efficient sensitizing of lanthanide luminescence − in heterobimetallic or -trimetallic systems.…”