title: Synthesis and evaluation of a 125I-labeled iminodihydroquinoline-derived tracer for imaging of voltage-gated sodium channels.
abstract: 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 (125)I-labeled analogue of WIN17317-3 and evaluated the potential of the tracer for imaging of VGSCs with SPECT. Automated patch clamp studies with CHO cells expressing the Nav1.2 isoform and displacement studies with [(3)H]BTX yielded comparable results for the non-radioactive iodinated iminodihydroquinoline and WIN17317-3. However, the (125)I-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.
authors.affiliation: Department of Chemistry and Institute of Nuclear Medicine, UCL, London, United Kingdom.
authors.forename: Carlos
authors.initials: C
authors.lastname: Pérez-Medina
authors.forename: Niral
authors.initials: N
authors.lastname: Patel
authors.forename: Mathew
authors.initials: M
authors.lastname: Robson
authors.forename: Mark F
authors.initials: MF
authors.lastname: Lythgoe
authors.forename: Erik
authors.initials: E
authors.lastname: Arstad
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D061567:Voltage-Gated Sodium Channel Blockers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D061566:Voltage-Gated Sodium Channels / Q000187:drug effects*
chemical_list: D007457:Iodine Radioisotopes; D011804:Quinolines; D061567:Voltage-Gated Sodium Channel Blockers; D061566:Voltage-Gated Sodium Channels; C094805:WIN 17317-3
keywords: Imaging; Iodine-125; SPECT; Voltage-gated sodium channel; WIN17317-3
references.citation: Genome Biol. 2003;4(3):207
references.pmid: 12620097
references.citation: Nat Med. 2004 Jul;10(7):685-92
references.pmid: 15229516
references.citation: Bioorg Med Chem. 2006 Sep 15;14(18):6307-13
references.pmid: 16777419
references.citation: Proc Natl Acad Sci U S A. 2004 May 25;101(21):8168-73
references.pmid: 15148385
references.citation: Org Biomol Chem. 2012 Dec 21;10(47):9474-80
references.pmid: 23117159
references.citation: J Neurol. 2006 Dec;253(12):1542-51
references.pmid: 17219031
references.citation: Biochemistry. 1999 Aug 24;38(34):11137-46
references.pmid: 10460170
references.citation: Brain Res. 1991 Aug 16;556(2):311-6
references.pmid: 1657307
references.citation: Mol Pharmacol. 1996 Dec;50(6):1672-9
references.pmid: 8967992
references.citation: J Med Chem. 1995 May 26;38(11):1877-83
references.pmid: 7540207
references.citation: Lancet Neurol. 2010 Apr;9(4):413-24
references.pmid: 20298965
references.citation: J Biol Chem. 1981 Sep 10;256(17):8922-7
references.pmid: 6114956
references.citation: J Clin Invest. 2005 Aug;115(8):1990-9
references.pmid: 16075039
references.citation: Neuron. 2000 Apr;26(1):13-25
references.pmid: 10798388
references.citation: Annu Rev Neurosci. 2010;33:325-47
references.pmid: 20367448
references.citation: J Neurophysiol. 2003 Nov;90(5):3566-71
references.pmid: 12904334
references.citation: Annu Rev Physiol. 2001;63:871-94
references.pmid: 11181979
references.citation: Digestion. 2008;77(2):108-17
references.pmid: 18391489
references.citation: J Neurol Sci. 2005 Jun 15;233(1-2):27-35
references.pmid: 15894334
references.citation: J Neurosci. 2012 Aug 8;32(32):10949-60
references.pmid: 22875929
references.citation: Mol Imaging Biol. 2003 Nov-Dec;5(6):376-89
references.pmid: 14667492
references.citation: Brain Pathol. 2007 Apr;17(2):230-42
references.pmid: 17388954
references.citation: J Med Chem. 2001 Jan 18;44(2):115-37
references.pmid: 11170622
references.citation: Epilepsia. 2002 Nov;43(11):1278-95
references.pmid: 12423377
references.citation: J Am Chem Soc. 2013 Jan 16;135(2):703-9
references.pmid: 23194416
references.citation: J Neurosci. 2006 Oct 4;26(40):10100-9
references.pmid: 17021166
references.citation: J Clin Invest. 2005 Aug;115(8):2010-7
references.pmid: 16075041
references.citation: J Med Chem. 1978 Mar;21(3):268-72
references.pmid: 628002
references.citation: J Neurosci. 2003 Dec 10;23(36):11289-95
references.pmid: 14672992
references.citation: J Comp Neurol. 2005 May 30;486(2):117-31
references.pmid: 15844213
references.citation: Neuroreport. 2002 Oct 28;13(15):1909-12
references.pmid: 12395089
references.citation: Assay Drug Dev Technol. 2008 Dec;6(6):765-80
references.pmid: 19090691
references.citation: Brain Res. 1991 May 10;548(1-2):334-7
references.pmid: 1651145