Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 23, Issue 18, Pages 5170-5173Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2013.07.014
Keywords
SPECT; Voltage-gated sodium channel; WIN17317-3; Iodine-125; Imaging
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Funding
- Department of Health's NIHR Biomedical Research Centres funding scheme
- Medical Research Council
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In vivo imaging of voltage-gated sodium channels (VGSCs) can potentially provide insights into the activation of neuronal pathways and aid the diagnosis of a number of neurological diseases. The iminodihydroquinoline WIN17317-3 is one of the most potent sodium channel blockers reported to date and binds with high affinity to VGSCs throughout the rat brain. We have synthesized a I-125-labeled analogue of WIN17317-3 and evaluated the potential of the tracer for imaging of VGSCs with SPEC. Automated patch clamp studies with CHO cells expressing the Na(v)1.2 isoform and displacement studies with [H-3]BTX yielded comparable results for the non-radioactive iodinated iminodihydroquinoline and WIN17317-3. However, the I-125-labeled tracer was rapidly metabolized in vivo, and suffered from low brain uptake and high accumulation of radioactivity in the intestines. The results suggest that iminodihydroquinolines are poorly suited for tracer development. (C) 2013 Elsevier Ltd. All rights reserved.
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