Molecular-recognition architectures and emerging probe strategies for neurotransmitter chemical sensing

Monitoring neurotransmitter dynamics in the brain with high spatial and temporal fidelity is essential for understanding neural circuit function and dysfunction. Although detection technologies have advanced, the molecular recognition elements that initiate sensing still largely define selectivity, speed, and in vivo performance. Here we focus on rapidly evolving molecular-recognition architectures for small-molecule neurotransmitter probes. Moving beyond simple lock-and-key motifs, we compare receptor-inspired binding sites, reaction-driven chemistries, conformational switches, supramolecular host-guest complexes, and engineered proteins through four performance criteria: molecular selectivity, response speed, signal-reporting mechanisms, and in vivo stability. We also highlight how these architectures interface with optical and electrochemical readouts to enable real-time measurements in complex tissue. By framing recent advances within a common structure-performance landscape, this Perspective provides a chemistry-centric guide for designing next-generation molecular tools to interrogate neurotransmitter signaling in the brain.