Noninvasive Quantification of Metabotropic Glutamate Receptor Type 1 with [11C]ITDM: a Small-Animal PET Study

Because of its role in multiple central nervous system (CNS) pathways, metabotropic glutamate receptor type 1 (mGluR1) is a crucial target in the development of pharmaceuticals for CNS disorders. N-[4-[6-(isopropylamino)-pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[11C]-methylbenzamide ([11C]ITDM) was recently developed as a positron emission tomography (PET) ligand for mGluR1. To devise a method for measurement of the binding potential (BP ND ) of [11C]ITDM to mGluR1, reference tissue methods aimed at replacing measurement of the arterial input function are desirable. In this study, we evaluated a noninvasive quantification method of mGluR1 with [11C]ITDM, demonstrating its accuracy using Huntington disease model R6/2 mice. The BP ND measurements based on the Logan reference (Logan Ref) method have closely approximated that based on the arterial input method. We performed PET analysis with Logan Ref to assess its accuracy in quantifying the decline of mGluR1 expression in R6/2 mice. Significant decreases in BP ND values in R6/2 mice were detected in cerebellum, thalamus, striatum, and cingulate cortex. We compared autoradiographs of R6/2 mouse brain sections with immunohistochemical images, and found a close correlation between changes in radioactive signal intensity and degree of mGluR1 expression. In conclusion, [11C]ITDM-PET is a promising tool for in vivo quantification of mGluR1 expression.

[1]  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.

[2]  Mark E. Schmidt,et al.  Human PET studies of metabotropic glutamate receptor subtype 5 with 11C-ABP688. , 2007, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[3]  M. Takei,et al.  Sensitive measurement of positron emitters eluted from HPLC. , 2001, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[4]  T. Dawson,et al.  Differential localization of phosphoinositide-linked metabotropic glutamate receptor (mGluR1) and the inositol 1,4,5-trisphosphate receptor in rat brain , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[5]  P. Calabresi,et al.  Selective Blockade of Type-1 Metabotropic Glutamate Receptors Induces Neuroprotection by Enhancing Gabaergic Transmission , 2001, Molecular and Cellular Neuroscience.

[6]  N. Volkow,et al.  Distribution Volume Ratios without Blood Sampling from Graphical Analysis of PET Data , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[7]  Albert D. Windhorst,et al.  Radiosynthesis and preclinical evaluation of ( 11 C) , 2013 .

[8]  Mark Schmidt,et al.  Quantitative evaluation of 11C-ABP688 as PET ligand for the measurement of the metabotropic glutamate receptor subtype 5 using autoradiographic studies and a beta-scintillator , 2007, NeuroImage.

[9]  R. Duvoisin,et al.  Role of the Second and Third Intracellular Loops of Metabotropic Glutamate Receptors in Mediating Dual Signal Transduction Activation* , 1998, The Journal of Biological Chemistry.

[10]  R. Mott,et al.  Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation , 1997, Nature Genetics.

[11]  Brett Connolly,et al.  Species differences in mGluR5 binding sites in mammalian central nervous system determined using in vitro binding with [18F]F-PEB. , 2007, Nuclear medicine and biology.

[12]  J. Trojanowski,et al.  In Vivo Positron Emission Tomographic Imaging of Glial Responses to Amyloid-β and Tau Pathologies in Mouse Models of Alzheimer's Disease and Related Disorders , 2011, The Journal of Neuroscience.

[13]  C. Parsons,et al.  Neuroprotective activity of selective mGlu1 and mGlu5 antagonists in vitro and in vivo. , 2007, European journal of pharmacology.

[14]  Yuichiro Yoshida,et al.  Visualization of early infarction in rat brain after ischemia using a translocator protein (18kDa) PET ligand [11C]DAC with ultra-high specific activity , 2011, NeuroImage.

[15]  M. Mintun,et al.  A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography , 1984, Annals of neurology.

[16]  D J Brooks,et al.  Comparison of Methods for Analysis of Clinical [11C]Raclopride Studies , 1996, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[17]  Xiao-Jiang Li,et al.  Huntingtin-protein interactions and the pathogenesis of Huntington's disease. , 2004, Trends in genetics : TIG.

[18]  F. Bordi,et al.  Group I metabotropic glutamate receptors: implications for brain diseases , 1999, Progress in Neurobiology.

[19]  S. Nakanishi,et al.  Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGluRl, in transfected CHO cells , 1992, Neuron.

[20]  F. Tortella,et al.  Selective mGluR5 receptor antagonist or agonist provides neuroprotection in a rat model of focal cerebral ischemia , 2001, Brain Research.

[21]  P. Conn,et al.  Distinct physiological roles of the Gq‐coupled metabotropic glutamate receptors co‐expressed in the same neuronal populations , 2002, Journal of cellular physiology.

[22]  S. W. Davies,et al.  Exon 1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice , 1996, Cell.

[23]  J. Maeda,et al.  Development of N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methyl-4-[11C]methylbenzamide for positron emission tomography imaging of metabotropic glutamate 1 receptor in monkey brain. , 2012, Journal of medicinal chemistry.

[24]  P. Calabresi,et al.  Enhancement of NMDA responses by group I metabotropic glutamate receptor activation in striatal neurones , 1997, British journal of pharmacology.

[25]  L. Crepaldi,et al.  Metabotropic Glutamate 1 Receptor: Current Concepts and Perspectives , 2008, Pharmacological Reviews.

[26]  S. W. Davies,et al.  Altered brain neurotransmitter receptors in transgenic mice expressing a portion of an abnormal human huntington disease gene. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[27]  A. Lammertsma,et al.  Simplified Reference Tissue Model for PET Receptor Studies , 1996, NeuroImage.

[28]  Ming-Rong Zhang,et al.  In Vivo Measurement of the Affinity and Density of Metabotropic Glutamate Receptor Subtype 1 in Rat Brain Using 18F-FITM in Small-Animal PET , 2012, The Journal of Nuclear Medicine.

[29]  R A Challiss,et al.  Structural, signalling and regulatory properties of the group I metabotropic glutamate receptors: prototypic family C G-protein-coupled receptors. , 2001, The Biochemical journal.

[30]  M. Hata,et al.  Discovery and in vitro and in vivo profiles of 4-fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide as novel class of an orally active metabotropic glutamate receptor 1 (mGluR1) antagonist. , 2009, Bioorganic & medicinal chemistry letters.

[31]  E. Esposito,et al.  Role of 5-HT(2C) receptors in the control of central dopamine function. , 2001, Trends in pharmacological sciences.

[32]  P. Herscovitch,et al.  Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency , 2009, Neurology.

[33]  Seiji Tamura,et al.  Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models , 2008, Brain Research.

[34]  Young T. Hong,et al.  Validation of reference tissue modelling for [11C]flumazenil positron emission tomography following head injury , 2011, Annals of nuclear medicine.

[35]  A. Young.  Huntingtin in health and disease. , 2003, The Journal of clinical investigation.