Progression of obsessive compulsive disorder-like grooming in Sapap3 knockout mice: A longitudinal [¹¹C]ABP688 PET...

We aimed to evaluate [3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-0-¹¹C-methyloxime] ([¹¹C]ABP688) small animal positron emission tomography (μPET) as a biomarker to visualize possible longitudinal changes in metabotropic glutamate receptor 5 (mGluR5) availability in the brain of SAP90/PSD-95 associated protein 3 (Sapap3) knockout (ko) mice, showing obsessive compulsive disorder (OCD)-like behavior.

Alongside the assessment of grooming, we performed [¹¹C]ABP688 μPET/CT imaging in wildtype (wt; n=10) and ko (n=11) mice both at 3 and 9 months. Using the simplified reference tissue method (SRTM), the nondisplaceable binding potential (BP_ND) was calculated representing the in vivo availability of the metabotropic glutamate receptor 5 (mGluR5) in the brain with the cerebellum as a reference region. Longitudinal voxel-based statistical parametric mapping (SPM) was performed on BP_ND images. Results were verified using [¹¹C]ABP688 ex vivo autoradiography, [³H]ABP688 in vitro autoradiography, and mGluR5 immunohistochemistry.

Cross-sectional comparisons revealed significantly increased grooming parameters in ko animals, at both time points. A significant longitudinal increase in % grooming duration (+268.25%; p<0.05) reflected aggravation of this behavior in ko mice. [¹¹C]ABP688 μPET revealed significantly lower mGluR5 availability in the cortex, striatum, hippocampus, and amygdala of ko mice at both ages. A significant longitudinal BP_ND decline was present for ko mice (p<0.01: cortex -17.14%, striatum -19.82%, amygdala -23.57%; p<0.05: hippocampus -15.53%), which was confirmed by SPM (p<0.01).

Sapap3 ko mice show a decline in mGluR5 availability in OCD relevant brain regions parallel to the worsening of OCD-like behavior. This demonstrates a potential role for [¹¹C]ABP688 PET as a biomarker to monitor disease progression in vivo.