Direct visualization of an antidepressant analog using surface-enhanced Raman scattering in the brain.

Atsushi Kimishima,Naoyuki Kotoku,Masayoshi Arai,Masafumi Minoshima,Katsumasa Fujita,Kosuke Higashino,Satoshi Kawata,Kaoru Seiriki,Hitoshi Hashimoto,Yukio Ago,Kazuki Bando,Atsushi Kasai,Kazuya Kikuchi,Masato Tanuma,Kazuo Harada

doi:10.1172/jci.insight.133348

Atsushi Kimishima, Naoyuki Kotoku + Show 13 more

Open Access

https://doi.org/10.1172/jci.insight.133348

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Journal: JCI insight	Publication Date: Mar 26, 2020
Citations: 14	License type: cc-by

Abstract

Detailed spatial information of low-molecular weight compound distribution, especially in the brain, is crucial to understanding their mechanism of actions. Imaging techniques that can directly visualize drugs in the brain at a high resolution will complement existing tools for drug distribution analysis. Here, we performed surface-enhanced Raman scattering (SERS) imaging using a bioorthogonal alkyne tag to visualize drugs directly in situ at a high resolution. Focusing on the selective serotonin reuptake inhibitor S-citalopram (S-Cit), which possesses a nitrile group, we substituted an alkynyl group into its structure and synthesized alkynylated S-Cit (Alk-S-Cit). The brain transitivity and the serotonin reuptake inhibition of Alk-S-Cit were not significantly different as compared with S-Cit. Alk-S-Cit was visualized in the coronal mouse brain section using SERS imaging with silver nanoparticles. Furthermore, SERS imaging combined with fluorescence microscopy allowed Alk-S-Cit to be visualized in the adjacent neuronal membranes, as well as in the brain vessel and parenchyma. Therefore, our multimodal imaging technique is an effective method for detecting low-molecular weight compounds in their original tissue environment and can potentially offer additional information regarding the precise spatial distribution of such drugs.

Highlights

Determining the tissue distribution of drugs at their intended target is essential to understanding how these drugs exert their effects
Whereas the application of commonly used fluorophores with low–molecular weight compounds carries the risk of changing the pharmacokinetics and pharmacodynamics of the drugs, the small molecular size of the alkynyl group means it can be appended to these compounds without significantly altering their biological properties [16]
It has been reported that the cell nuclei in cultured cells were imaged previously by using spontaneous Raman spectroscopy and EdU (5-ethynyl-2’-deoxyuridine), a thymidine analog with an alkynyl group [14, 16]

Summary

Introduction

Determining the tissue distribution of drugs at their intended target is essential to understanding how these drugs exert their effects. The brain is a complex organ and is anatomically defined into numerous regions that regulate distinct functions [1, 2], making it even more important to understand the tissue distribution of drugs such as antidepressants that act on the CNS. For determining the drug distribution in the brain, imaging techniques are considered to be powerful tools. The tissue distribution of CNS drugs such as selective serotonin reuptake inhibitors (SSRIs) is often studied using imaging techniques including PET and mass spectrometry imaging (MSI).

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