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Bioorg Med Chem. 2016 Oct 1;24(19):4759-4765. doi: 10.1016/j.bmc.2016.08.020. Epub 2016 Aug 13.

Towards the PET radiotracer for p75 neurotrophin receptor: [(11)C]LM11A-24 shows biological activity in vitro, but unfavorable ex vivo and in vivo profile.

Author information

1
University of British Columbia, 3187 University Way, Kelowna, BC V1V1V7, Canada; Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A2B4, Canada.
2
Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Douglas Mental Health University Institute, 6875 Boulevard LaSalle, Montreal, QC H4H 1R3, Canada.
3
Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A2B4, Canada.
4
Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A2B4, Canada; Translational Neuroimaging Laboratory, McGill University Research Centre for Studies in Aging, Douglas Mental Health University Institute, 6875 Boulevard LaSalle, Montreal, QC H4H 1R3, Canada.
5
University of British Columbia, 3187 University Way, Kelowna, BC V1V1V7, Canada.
6
Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, QC H3A2B4, Canada. Electronic address: alexey.kostikov@mcgill.ca.

Abstract

Mature neurotrophins as well as their pro forms are critically involved in the regulation of neuronal functions. They are signaling through three distinct types of receptors: tropomyosin receptor kinase family (TrkA/B/C), p75 neurotrophin receptor (p75(NTR)) and sortilin. Aberrant expression of p75(NTR) in the CNS is implicated in a variety of neurodegenerative diseases, including Alzheimer's disease. The goal of this work was to evaluate one of the very few reported p75(NTR) small molecule ligands as a lead compound for development of novel PET radiotracers for in vivo p75(NTR) imaging. Here we report that previously described ligand LM11A-24 shows significant inhibition of carbachol-induced persistent firing (PF) of entorhinal cortex (EC) pyramidal neurons in wild-type mice via selective interaction with p75(NTR). Based on this electrophysiological assay, the compound has very high potency with an EC50<10nM. We optimized the radiosynthesis of [(11)C]LM11A-24 as the first attempt to develop PET radioligand for in vivo imaging of p75(NTR). Despite some weak interaction with CNS tissues, the radiolabeled compound showed unfavorable in vivo profile presumably due to high hydrophilicity.

KEYWORDS:

Electrophysiological assay; Imaging; Neurotrophin factors; Positron emission tomography; p75 neurotrophin receptor

PMID:
27567078
DOI:
10.1016/j.bmc.2016.08.020
[Indexed for MEDLINE]

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