2. Academic Validation
  3. Molecular Design of SERTlight: A Fluorescent Serotonin Probe for Neuronal Labeling in the Brain

Molecular Design of SERTlight: A Fluorescent Serotonin Probe for Neuronal Labeling in the Brain

  • J Am Chem Soc. 2024 Apr 10;146(14):9564-9574. doi: 10.1021/jacs.3c11617.
Wei-Li Lee 1,  Xavier Westergaard 2 3,  Christopher Hwu 1,  Jennifer Hwu 1,  Tomas Fiala 1 4,  Clay Lacefield 3 5,  Umed Boltaev 1,  Adriana M Mendieta 1,  Lisa Lin 3 6,  Mark S Sonders 3 7,  Keaon R Brown 1,  Keer He 1,  Wesley B Asher 3 6,  Jonathan A Javitch 3 6 7,  David Sulzer 3 8 6 7,  Dalibor Sames 1 9
Affiliations

Affiliations

  • 1 Department of Chemistry, Columbia University, New York, New York 10027, United States.
  • 2 Department of Biological Sciences, Columbia University, New York, New York 10027, United States.
  • 3 Department of Psychiatry, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 4 Laboratory of Organic Chemistry, ETH Zürich, D-CHAB, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland.
  • 5 Division of Systems Neuroscience, New York State Psychiatric Institute, New York, New York 10032, United States.
  • 6 Department of Molecular Pharmacology and Therapeutics, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 7 Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York 10032, United States.
  • 8 Department of Neurology, Columbia University Irving Medical Center, New York, New York 10032, United States.
  • 9 Zuckerman Mind Brain Behavior Institute, Columbia University, New York, New York 10027, United States.
PMID: 38557024 DOI: 10.1021/jacs.3c11617
Abstract

The serotonergic transmitter system plays fundamental roles in the nervous system in neurotransmission, synaptic plasticity, pathological processes, and therapeutic effects of antidepressants and psychedelics, as well as in the gastrointestinal and circulatory systems. We introduce a novel small molecule fluorescent agent, termed SERTlight, that specifically labels serotonergic neuronal cell bodies, dendrites, and axonal projections as a Serotonin Transporter (SERT) fluorescent substrate. SERTlight was developed by an iterative molecular design process, based on an aminoethyl-quinolone system, to integrate structural elements that impart SERT substrate activity, sufficient fluorescent brightness, and a broad absence of pharmacological activity, including at serotonin (5-hydroxytryptamine, 5HT) receptors, Other G protein-coupled receptors (GPCRs), ion channels, and monoamine transporters. The high labeling selectivity is not achieved by high affinity binding to SERT itself but rather by a sufficient rate of SERT-mediated transport of SERTlight, resulting in accumulation of these molecules in 5HT neurons and yielding a robust and selective optical signal in the mammalian brain. SERTlight provides a stable signal, as it is not released via exocytosis nor by reverse SERT transport induced by 5HT releasers such as MDMA. SERTlight is optically, pharmacologically, and operationally orthogonal to a wide range of genetically encoded sensors, enabling multiplexed imaging. SERTlight enables labeling of distal 5HT axonal projections and simultaneous imaging of the release of endogenous 5HT using the GRAB5HT sensor, providing a new versatile molecular tool for the study of the serotonergic system.

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