Evaluation of the potassium channel tracer [18F]3F4AP in rhesus macaques

Demyelination causes slowed or failed neuronal conduction and is a driver of disability in multiple sclerosis and other neurological diseases. Currently, the gold standard for imaging demyelination is MRI, but despite its high spatial resolution and sensitivity to demyelinated lesions, it remains challenging to obtain specific and quantitative measures of molecular changes involved in demyelination. To understand the contribution of demyelination in different diseases and to assess the efficacy of myelin-repair therapies, it is critical to develop new in vivo imaging tools sensitive to changes induced by demyelination. Upon demyelination, axonal K+ channels, normally located underneath the myelin sheath, become exposed and increase in expression, causing impaired conduction. Here, we investigate the properties of the K+ channel PET tracer [ 18 F]3F4AP in primates and its sensitivity to a focal brain injury that occurred three years prior to imaging. [ 18 F]3F4AP exhibited favorable properties for brain imaging including high brain penetration, high metabolic stability, high plasma availability, high reproducibility, high specificity, and fast kinetics. [ 18 F]3F4AP showed preferential binding in areas of low myelin content as well as in the previously injured area. Sensitivity of [ 18 F]3F4AP for the focal brain injury was higher than [ 18 F]FDG, [ 11 C]PiB, and [ 11 C]PBR28, and compared favorably to currently used MRI methods.

[1]  C. Buchpiguel,et al.  [11C]PIB PET imaging can detect white and grey matter demyelination in a non-human primate model of progressive multiple sclerosis. , 2019, Multiple sclerosis and related disorders.

[2]  A. Bravin,et al.  Structure-activity relationship studies of four novel 4-aminopyridine K+ channel blockers , 2019, Scientific Reports.

[3]  Ninon Burgos,et al.  New advances in the Clinica software platform for clinical neuroimaging studies , 2019 .

[4]  D. Reich,et al.  Detecting Demyelination by PET: The Lesion as Imaging Target , 2018, Molecular imaging.

[5]  D. Reich,et al.  An efficient new method for the synthesis of 3-[18 F]fluoro-4-aminopyridine via Yamada-Curtius rearrangement. , 2018, Journal of labelled compounds & radiopharmaceuticals.

[6]  Chin-Tu Chen,et al.  Development of a PET radioligand for potassium channels to image CNS demyelination , 2018, Scientific Reports.

[7]  H. Johansen-Berg,et al.  Advances in noninvasive myelin imaging , 2017, Developmental neurobiology.

[8]  Mohammed P. I. Bhuiyan,et al.  Automated Radiochemical Synthesis of [18F]3F4AP: A Novel PET Tracer for Imaging Demyelinating Diseases , 2017, Journal of visualized experiments : JoVE.

[9]  David A. Leopold,et al.  A population MRI brain template and analysis tools for the macaque , 2017, NeuroImage.

[10]  B. Bodini,et al.  Imaging Central Nervous System Demyelination and Remyelination by Positron-Emission Tomography , 2016, Brain plasticity.

[11]  E. Ullian,et al.  Dynamic Modulation of Myelination in Response to Visual Stimuli Alters Optic Nerve Conduction Velocity , 2016, The Journal of Neuroscience.

[12]  Brian Quinn,et al.  Radiation dosimetry of 18F-FDG PET/CT: incorporating exam-specific parameters in dose estimates , 2016, BMC Medical Imaging.

[13]  S. Kasner,et al.  Dalfampridine in chronic sensorimotor deficits after ischemic stroke: A proof of concept study. , 2015, Journal of rehabilitation medicine.

[14]  M. Nader,et al.  Improved Automated Radiosynthesis of [11C]PBR28 , 2015, Scientia pharmaceutica.

[15]  R. Franklin,et al.  The translational biology of remyelination: Past, present, and future , 2014, Glia.

[16]  S. Ovsepian,et al.  Disruption of Myelin Leads to Ectopic Expression of KV1.1 Channels with Abnormal Conductivity of Optic Nerve Axons in a Cuprizone-Induced Model of Demyelination , 2014, PloS one.

[17]  G. Fakhri,et al.  Automation of column-switching HPLC for analysis of radiopharmaceuticals and their metabolites in plasma , 2013 .

[18]  Jan-Mendelt Tillema,et al.  Neuroradiological evaluation of demyelinating disease , 2013, Therapeutic advances in neurological disorders.

[19]  Maria F. Sassano,et al.  Automated design of ligands to polypharmacological profiles , 2012, Nature.

[20]  S. Zamvil,et al.  K+ channel alterations in the progression of experimental autoimmune encephalomyelitis , 2012, Neurobiology of Disease.

[21]  P. Scott,et al.  Synthesis of [18F]‐Fluorodeoxyglucose ([18F]FDG) , 2012 .

[22]  Massimo Filippi,et al.  MR imaging of multiple sclerosis. , 2011, Radiology.

[23]  Robert J Fox,et al.  Advanced MRI in multiple sclerosis: current status and future challenges. , 2011, Neurologic clinics.

[24]  S. Lehéricy,et al.  Imaging central nervous system myelin by positron emission tomography in multiple sclerosis using [methyl‐11C]‐2‐(4′‐methylaminophenyl)‐ 6‐hydroxybenzothiazole , 2011, Annals of neurology.

[25]  C. Flask,et al.  A novel PET marker for in vivo quantification of myelination. , 2010, Bioorganic & medicinal chemistry.

[26]  Klaus-Armin Nave,et al.  Myelination and the trophic support of long axons , 2010, Nature Reviews Neuroscience.

[27]  J. O'Brien,et al.  Quantification of myelin loss in frontal lobe white matter in vascular dementia, Alzheimer’s disease, and dementia with Lewy bodies , 2010, Acta Neuropathologica.

[28]  Victor W Pike,et al.  PET radiotracers: crossing the blood-brain barrier and surviving metabolism. , 2009, Trends in pharmacological sciences.

[29]  Keith A. Johnson,et al.  Amyloid Deposition Is Associated with Impaired Default Network Function in Older Persons without Dementia , 2009, Neuron.

[30]  L. Krupp,et al.  Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial , 2009, The Lancet.

[31]  R. Fields,et al.  White matter in learning, cognition and psychiatric disorders , 2008, Trends in Neurosciences.

[32]  Rohit Bakshi,et al.  MRI in multiple sclerosis: current status and future prospects , 2008, The Lancet Neurology.

[33]  Robert B. Innis,et al.  Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation , 2008, NeuroImage.

[34]  Masahiro Fujita,et al.  Brain and whole-body imaging in nonhuman primates of [11C]PBR28, a promising PET radioligand for peripheral benzodiazepine receptors , 2008, NeuroImage.

[35]  R. P. Maguire,et al.  Consensus Nomenclature for in vivo Imaging of Reversibly Binding Radioligands , 2007, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[36]  W. L. Benedict,et al.  Multiple Sclerosis , 2007, Journal - Michigan State Medical Society.

[37]  J. Girault,et al.  Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis. , 2006, Brain : a journal of neurology.

[38]  Alexander A Velumian,et al.  Functional changes in genetically dysmyelinated spinal cord axons of shiverer mice: role of juxtaparanodal Kv1 family K+ channels. , 2006, Journal of neurophysiology.

[39]  Heike Wulff,et al.  International Union of Pharmacology. LIII. Nomenclature and Molecular Relationships of Voltage-Gated Potassium Channels , 2005, Pharmacological Reviews.

[40]  B. Rudy,et al.  International Union of Pharmacology. LIII. Nomenclature and Molecular Relationships of Voltage-Gated Potassium Channels , 2005, Pharmacological Reviews.

[41]  P. Calabresi,et al.  The voltage-gated potassium channel Kv1.3 is highly expressed on inflammatory infiltrates in multiple sclerosis brain. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[42]  S. Scherer,et al.  Acute demyelination disrupts the molecular organization of peripheral nervous system nodes , 2004, The Journal of comparative neurology.

[43]  Alan A. Wilson,et al.  A rapid one-step radiosynthesis of the β-amyloid imaging radiotracer N-methyl-[11C]2-(4′-methylaminophenyl)-6-hydroxybenzothiazole ([11C]-6-OH-BTA-1) , 2004 .

[44]  W. Klunk,et al.  Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound‐B , 2004, Annals of neurology.

[45]  K. Rhodes,et al.  Localization of voltage-gated ion channels in mammalian brain. , 2004, Annual review of physiology.

[46]  K. Jellinger,et al.  Preferential Loss of Myelin‐Associated Glycoprotein Reflects Hypoxia‐Like White Matter Damage in Stroke and Inflammatory Brain Diseases , 2003, Journal of neuropathology and experimental neurology.

[47]  Robert B. Innis,et al.  Strategies to Improve Neuroreceptor Parameter Estimation by Linear Regression Analysis , 2002, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[48]  C. Armstrong,et al.  A model for 4-aminopyridine action on K channels: similarities to tetraethylammonium ion action. , 2001, Biophysical journal.

[49]  D. Wong,et al.  Column-switching HPLC for the analysis of plasma in PET imaging studies. , 2000, Nuclear medicine and biology.

[50]  Mark Ellisman,et al.  Potassium Channel Distribution, Clustering, and Function in Remyelinating Rat Axons , 1998, The Journal of Neuroscience.

[51]  R. Nashmi,et al.  Changes in pharmacological sensitivity of the spinal cord to potassium channel blockers following acute spinal cord injury , 1996, Brain Research.

[52]  C. Marsden,et al.  Movement disorders in multiple sclerosis , 1995, Movement disorders : official journal of the Movement Disorder Society.

[53]  R I Grossman,et al.  Magnetization transfer: theory and clinical applications in neuroradiology. , 1994, Radiographics : a review publication of the Radiological Society of North America, Inc.

[54]  D. Wolfe,et al.  Preclinical trial of 4-aminopyridine in patients with chronic spinal cord injury , 1993, Paraplegia.

[55]  Paty Dw,et al.  Magnetic resonance in multiple sclerosis. , 1993 .

[56]  J. M. Ritchie,et al.  Molecular dissection of the myelinated axon , 1993, Annals of neurology.

[57]  David J. Schlyer,et al.  Graphical Analysis of Reversible Radioligand Binding from Time—Activity Measurements Applied to [N-11C-Methyl]-(−)-Cocaine PET Studies in Human Subjects , 1990, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[58]  Stephen G. Waxman,et al.  Demyelination in spinal cord injury , 1989, Journal of the Neurological Sciences.

[59]  C. Schauf,et al.  4‐Aminopyridine improves clinical signs in multiple sclerosis , 1987, Annals of neurology.

[60]  D. Paty,et al.  Neuroimaging in multiple sclerosis. , 1984, Neurologic clinics.

[61]  H. Bostock,et al.  Effects of 4-aminopyridine on normal and demyelinated mammalian nerve fibres , 1980, Nature.

[62]  H. Akaike.  A new look at the statistical model identification , 1974 .

[63]  E. Schafer,et al.  A summary of the acute toxicity of 4-aminopyridine to birds and mammals. , 1973, Toxicology and applied pharmacology.

[64]  Regina C. Armstrong,et al.  White matter involvement after TBI: Clues to axon and myelin repair capacity , 2016, Experimental Neurology.

[65]  R. Freifelder,et al.  Synthesis of meta-substituted [(18)F]3-fluoro-4-aminopyridine via direct radiofluorination of pyridine N-oxides. , 2016, Chemical communications.

[66]  M. Szente,et al.  Neocortical cytopathology in focal aminopyridine seizures as related to the intracortical diffusion of [3H] 4-aminopyridine , 2004, Acta Neuropathologica.

[67]  G. Scialfa,et al.  Magnetic resonance in multiple sclerosis , 2004, Neuroradiology.