Quantification of [11C]ABP688 binding in human brain using cerebellum as reference region: biological interpretation and limitations

Abstract

AbstractIn vitrodata from primates provide conflicting evidence about the cerebellum’s suitability as a reference region for quantifying type 5 metabotropic glutamate receptor (mGluR5) binding parameters with positron emission tomography (PET). To address this, we first measured mGluR5 density in postmortem human cerebellum using [3H]ABP688 autoradiography (n=5) and immunohistochemistry (n=6). Next,in vivoexperiments were conducted in healthy volunteers (n=6) using a high-resolution PET scanner (HRRT) to compare [11C]ABP688 binding potential (BPND) values obtained with reference tissue methods and the two-tissue compartment model vs. metabolite-corrected arterial input function. The postmortem data showed that, relative to the hippocampus, the cerebellum had 26% less mGluR5 immunoreactivity and 94% fewer [3H]ABP688 binding sites.In vivobrain regional [11C]ABP688 BPNDvalues using the cerebellum as a reference region were highly correlated with BPNDvalues and distribution volumes derived by arterial input methods (R2> 0.9). The absence of cerebellar allosteric binding sites might reflect the presence of distinct mGluR5 isoforms or conformational state. Together with our PET data, these results support the proposition that [11C]ABP688 BPNDusing cerebellum as a reference region provides accurate quantification of mGluR5 allosteric bindingin vivo.