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

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-<i>O</i>-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. <b>Methods:</b>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 (BP_ND) 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 BP_ND images. Postmortem validation of mGluR5 level and neuronal density was performed on the mice at 6 mo old. <b>Results:</b> The ¹¹C-ABP688 BP_ND 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; <i>P</i> < 0.001 for all) and in the cortex (-9.8%, -10.2%, and -10.6%, respectively; <i>P</i> < 0.01 for all), when compared with WT animals. Longitudinal changes in ¹¹C-ABP688 BP_ND were also found in heterozygous mice, showing a reduction at 13 mo compared with 6 mo (-10.4%, <i>P</i> < 0.05). SPM analysis confirmed reduced BP_ND 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%; <i>P</i> < 0.01) and cortex (-16.6%; <i>P</i> < 0.05) in heterozygous mice, whereas no difference in neuronal density was found. <b>Conclusion:</b> 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.