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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 ether-based binding sites properties to increase the affinity toward 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 toward 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 toward 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 toward ZNTs is greatly affected by the remote pendant on the azacrown derivative.

We report two macrocyclic ligands based on a 1,7-diaza-12-crown-4 platform functionalized with acetate (tO2DO2A2−) or piperidineacetamide (tO2DO2AMPip) pendant arms and a detailed characterization of the corresponding Mn(II) complexes. The X−ray structure of [Mn(tO2DO2A)(H2O)]·2H2O shows that the metal ion is coordinated by six donor atoms of the macrocyclic ligand and one water molecule, to result in seven-coordination. The Cu(II) analogue presents a distorted octahedral coordination environment. The protonation constants of the ligands and the stability constants of the complexes formed with Mn(II) and other biologically relevant metal ions (Mg(II), Ca(II), Cu(II) and Zn(II)) were determined using potentiometric titrations (I = 0.15 M NaCl, T = 25 °C). The conditional stabilities of Mn(II) complexes at pH 7.4 are comparable to those reported for the cyclen-based tDO2A2− ligand. The dissociation of the Mn(II) chelates were investigated by evaluating the rate constants of metal exchange reactions with Cu(II) under acidic conditions (I = 0.15 M NaCl, T = 25 °C). Dissociation of the [Mn(tO2DO2A)(H2O)] complex occurs through both proton− and metal−assisted pathways, while the [Mn(tO2DO2AMPip)(H2O)] analogue dissociates through spontaneous and proton-assisted mechanisms. The Mn(II) complex of tO2DO2A2− is remarkably inert with respect to its dissociation, while the amide analogue is significantly more labile. The presence of a water molecule coordinated to Mn(II) imparts relatively high relaxivities to the complexes. The parameters determining this key property were investigated using 17O NMR (Nuclear Magnetic Resonance) transverse relaxation rates and 1H nuclear magnetic relaxation dispersion (NMRD) profiles.

Up conversion is an Anti-Stokes luminescent process by which photons of low energy are piled up to generate light at a higher energy. Here, the authors report a supramolecular assembly of fluoride-bridged erbium complexes which exhibit this behaviour in D2O solution at room temperature.