Molecular Imaging of mGluR5 Availability with [¹¹C]ABP68 in Glutaminase Heterozygous Mice

Many PET tracers enable determination of fluctuations in neurotransmitter release, yet glutamate specifically can not be visualized in a noninvasive manner. Several studies point to the possibility of visualizing fluctuations in glutamate release by changes in affinity of the mGluR5 radioligand [¹¹C]ABP688. These studies use pharmacological challenges to alter glutamate levels, and so probe release, but have not measured chronic alterations in receptor occupancy due to altered neurotransmission relevant to chronic neuropsychiatric disorders or their treatment. In this regard, the GLS1 heterozygous mouse has known reductions in activity of the glutamate-synthetic enzyme glutaminase, brain glutamate levels and release. We imaged this model to elucidate glutamatergic systems. Dynamic [¹¹C]ABP688 microPET scans were performed for mGluR5. Western blot was used as an ex vivo validation. No significant differences were found in BP_ND between WT and GLS1 Hets. SPM showed voxel-wise increased in BP_ND in GLS1 Hets compared to WT consistent with lower synaptic glutamate. This was not due to alterations in mGluR5 levels, as western blot results showed lower mGluR5 levels in GLS1 Hets. We conclude that because of the chronic glutaminase deficiency and subsequent decrease in glutamate, the mGluR5 protein levels are lowered. Due to these decreased endogenous glutamate levels, however, there is increased [¹¹C]ABP688 binding to the allosteric site in selected regions. We speculate that lower endogenous glutamate leads to less conformational change to the receptors, and thus higher availability of the binding site. The lower mGluR5 levels, however, lessen [¹¹C]ABP688 binding in GLS1 Hets, in part masking the increase in binding due to diminished endogenous glutamate levels as confirmed with voxel-wise analysis.