In-depth Study of a Novel Class of Ditopic Gadolinium(III)-based MRI Probes Sensitive to Zwitterionic Neurotransmitters

Abstract

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 T 1 -weighted relaxometric titrations. We prepared and investigated six Gd 3+ 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 r 1 of around 70%. In contrast, hosts with negatively charged substituents exhibited lower decrease in r 1 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.

Translating a Low‐Molecular‐Weight MRI Probe Sensitive to Amino Acid Neurotransmitters into a PAMAM Dendrimer Conjugate: The Impact of Conjugation

“…The obtained data were plotted as r 1 and r 2 values versus the amount of added analyte and subsequently the K a values were acquired from the non‐linear fitting of the r 1 values (Table ). As expected, the obtained r 1 and r 2 relaxometric curves displayed downward trends, which are typical for the q ‐modulated strategy that operates via a turn‐off mechanism, implying water molecule displacement from the paramagnetic label (Figure ) . The PEGylated conjugate displayed absolute discrimination for the non‐zwitterionic ACh, while the competitor, HCO 3 − , induced a decrease in r 1 of 51% upon saturation, which is greater than values observed for the ZNTs, ranging between 34 and 40%.…”

Macrocyclic Pyclen-Based Gd3+ Complex with High Relaxivity and pH Response

“…A huge amount of research in the field of MRI contrast agents has been devoted to develop systems that present a response to relevant biochemical parameters, as for instance pH, − the concentration of biogenic cations − or neurotransmitters, − enzymatic activity, − or redox potential. − Among these physiological parameters, pH is considered to be an important biomarker of several diseases, including inflammatory processes and cancer. , Most pH-responsive Gd 3+ agents contain a group coordinated to the metal ion (i.e., sulfonamide, amine, p -nitrophenol, phosphonate, etc.) that is detached upon protonation close to physiological pH.…”