Neurotransmitter-Responsive Nanosensors for <i>T</i>₂-Weighted Magnetic Resonance Imaging

TLDR

Neurotransmitter‑sensitive MRI contrast agents have been used to map brain signaling, but T1‑weighted paramagnetic sensors require micromolar concentrations that perturb neurochemistry. The study introduces an alternative architecture using superparamagnetic iron oxide nanoparticles conjugated to tethered neurotransmitter analogs and engineered binding proteins to detect neurotransmitters. The sensors function by clustering of nanoparticle conjugates that is reversibly disrupted by neurotransmitter binding, thereby altering T2‑weighted MRI signals, as demonstrated with dopamine and serotonin analogs and competitive binding proteins. The dopamine and serotonin sensors exhibit up to 20 % target‑selective relaxivity changes at sub‑endogenous concentrations, offering a promising minimally perturbative method for neurochemical imaging.

Abstract

Neurotransmitter-sensitive contrast agents for magnetic resonance imaging (MRI) have recently been used for mapping signaling dynamics in live animal brains, but paramagnetic sensors for T1-weighted MRI are usually effective only at micromolar concentrations that themselves perturb neurochemistry. Here we present an alternative molecular architecture for detecting neurotransmitters, using superparamagnetic iron oxide nanoparticles conjugated to tethered neurotransmitter analogs and engineered neurotransmitter binding proteins. Interactions between the nanoparticle conjugates result in clustering that is reversibly disrupted in the presence of neurotransmitter analytes, thus altering T2-weighted MRI signals. We demonstrate this principle using tethered dopamine and serotonin analogs, together with proteins selected for their ability to competitively bind either the analogs or the neurotransmitters themselves. Corresponding sensors for dopamine and serotonin exhibit target-selective relaxivity changes of up to 20%, while also operating below endogenous neurotransmitter concentrations. Semisynthetic magnetic particle sensors thus represent a promising path for minimally perturbative studies of neurochemical analytes.