Quantification of Metabotropic Glutamate Receptor 5 Availability With Both [11C]ABP688 and [18F]FPEB Positron Emission Tomography in the Sapap3 Knockout Mouse Model for Obsessive-Compulsive–like Behavior

Abstract

BackgroundThis study provides a first direct comparison between positron emission tomography radioligands targeting the allosteric site of the metabotropic glutamate receptor 5 (mGluR5): [11C]ABP688 and [18F]FPEB. A blocking paradigm was set up to substantiate the common binding site of both radioligands. Second, both radioligands were applied in Sapap3 knockout (KO) mice showing compulsive-like behavior characterized by a lower in vivo mGluR5 availability. MethodsFirst, wild-type mice (n = 7) received four position emission tomography/computed tomography scans: a [11C]ABP688 scan, a [18F]FPEB scan, and two blocking scans using cold FPEB and cold ABP688, respectively. A second experiment compared both radioligands in wild-type (n = 7) and KO (n = 10) mice. The simplified reference tissue model was used to calculate the nondisplaceable binding potential representing the in vivo availability of mGluR5 in the brain. ResultsUsing cold FPEB as a blocking compound for [11C]ABP688 micro–positron emission tomography and vice versa, we observed averaged global reductions in mGluR5 availability of circa 98% for [11C]ABP688 and 82%–96% for [18F]FPEB. For KOs, the [11C]ABP688 nondisplaceable binding potential was on average 25% lower compared with wild-type control mice (p < .0001–.001), while this was about 17% for [18F]FPEB (p < .05). ConclusionsThe current findings substantiate a common binding site and suggest a strong relationship between mGluR5 availability levels measured with both radioligands. In Sapap3 KO mice, a reduced mGluR5 availability could therefore be demonstrated with both radioligands. With [11C]ABP688, higher significance levels were achieved in more brain regions. These findings suggest [11C]ABP688 as a preferable radiotracer to quantify mGluR5 availability, as exemplified here in a model for compulsive-like behavior.