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Bioorg Med Chem Lett. 2018 Feb 1;28(3):371-377. doi: 10.1016/j.bmcl.2017.12.036. Epub 2017 Dec 17.

Development of fluorescence imaging probes for nicotinic acetylcholine α4β2 receptors.

Author information

1
Preclinical Imaging, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697, United States.
2
Department of Neurobiology and Behavior, University of California-Irvine, Irvine, CA 92697, United States.
3
Department of Neurobiology, University of Chicago, IL 60637, United States.
4
Preclinical Imaging, Department of Radiological Sciences, University of California-Irvine, Irvine, CA 92697, United States; Department of Biomedical Engineering, University of California-Irvine, Irvine, CA 92697, United States. Electronic address: j.mukherjee@uci.edu.

Abstract

Nicotinic acetylcholine α4β2 receptors (nAChRs) are implicated in various neurodegenerative diseases and smoking addiction. Imaging of brain high-affinity α4β2 nAChRs at the cellular and subcellular levels would greatly enhance our understanding of their functional role. Since better resolution could be achieved with fluorescent probes, using our previously developed positron emission tomography (PET) imaging agent [18F]nifrolidine, we report here design, synthesis and evaluation of two fluorescent probes, nifrodansyl and nifrofam for imaging α4β2 nAChRs. The nifrodansyl and nifrofam exhibited nanomolar affinities for the α4β2 nAChRs in [3H]cytisine-radiolabeled rat brain slices. Nifrofam labeling was observed in α4β2 nAChR-expressing HEK cells and was upregulated by nicotine exposure. Nifrofam co-labeled cell-surface α4β2 nAChRs, labeled with antibodies specific for a β2 subunit extracellular epitope indicating that nifrofam labels α4β2 nAChR high-affinity binding sites. Mouse brain slices exhibited discrete binding of nifrofam in the auditory cortex showing promise for examining cellular distribution of α4β2 nAChRs in brain regions.

KEYWORDS:

Fluorescence imaging; Nicotine; Nifene; Nifrodansyl; Nifrofam; Nifrolidine

PMID:
29277457
PMCID:
PMC6004331
DOI:
10.1016/j.bmcl.2017.12.036
[Indexed for MEDLINE]
Free PMC Article

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