Longitudinal Characterization of mGluR5 Using 11 C-ABP688 PET Imaging in the Q175 Mouse Model of Huntington Disease

J Nucl Med. 2018 Nov;59(11):1722-1727. doi: 10.2967/jnumed.118.210658. Epub 2018 May 24.

Abstract

Metabotropic glutamate receptor 5 (mGluR5) represents a potential therapeutic target for Huntington disease. Using 11C-ABP688 (3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11C-methyl-oxime), a noncompetitive and highly selective antagonist for mGluR5, we aimed to longitudinally characterize in vivo changes in mGluR5 by means of PET imaging in the Q175 mouse model of Huntington disease. Methods: 11C-ABP688 PET imaging, followed by a CT scan, was performed on 18 heterozygous mice and 18 wild-type (WT) littermates at 3 different time points (6, 9, and 13 mo old). 11C-ABP688 nondisplaceable binding potential (BPND) was calculated for each time point in striatum and cortex using the cerebellum as the reference region. In addition, voxel-based statistical parametric mapping (SPM) analysis was performed on BPND images. Postmortem validation of mGluR5 level and neuronal density was performed on the mice at 6 mo old. Results: The 11C-ABP688 BPND of heterozygous animals was significantly reduced at all time points in the striatum (-13.1%, -13.5%, and -14.2% at 6, 9, and 13 mo, respectively; P < 0.001 for all) and in the cortex (-9.8%, -10.2%, and -10.6%, respectively; P < 0.01 for all), when compared with WT animals. Longitudinal changes in 11C-ABP688 BPND were also found in heterozygous mice, showing a reduction at 13 mo compared with 6 mo (-10.4%, P < 0.05). SPM analysis confirmed reduced BPND in heterozygous compared with WT mice, as well as a time-related decline in 11C-ABP688 binding in the striatum of heterozygous mice. Postmortem analysis confirmed a mGluR5 decrease in both striatum (-36.6%; P < 0.01) and cortex (-16.6%; P < 0.05) in heterozygous mice, whereas no difference in neuronal density was found. Conclusion: In vivo imaging of mGluR5 using 11C-ABP688 PET/CT revealed a marked reduction in ligand binding in the striatum and cortex of heterozygous mice, compared with WT mice, as well as a temporal decline. This study suggests that 11C-ABP688 PET imaging is a potential biomarker to monitor the progression of, and therapeutic strategies for, Huntington disease.

Keywords: 11C-ABP688; Huntington disease; PET; Q175; mGluR5.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Carbon Radioisotopes / pharmacokinetics
  • Disease Models, Animal
  • Disease Progression
  • Heterozygote
  • Humans
  • Huntingtin Protein / genetics
  • Huntington Disease / diagnostic imaging*
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Longitudinal Studies
  • Male
  • Mice
  • Mice, Neurologic Mutants
  • Mice, Transgenic
  • Mutant Proteins / genetics
  • Oximes / pharmacokinetics*
  • Positron Emission Tomography Computed Tomography / methods
  • Pyridines / pharmacokinetics*
  • Radiopharmaceuticals / pharmacokinetics*
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors
  • Receptor, Metabotropic Glutamate 5 / metabolism*

Substances

  • 3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime
  • Biomarkers
  • Carbon Radioisotopes
  • Carbon-11
  • Grm5 protein, mouse
  • Htt protein, mouse
  • Huntingtin Protein
  • Mutant Proteins
  • Oximes
  • Pyridines
  • Radiopharmaceuticals
  • Receptor, Metabotropic Glutamate 5