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

Background: This 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.

Methods: First, 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.

Results: Using 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).

Conclusions: The 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.

Keywords: Metabotropic glutamate receptor 5; Obsessive-compulsive disorder; PET; Sapap3 knockout mouse model; [(11)C]ABP688; [(18)F]FPEB.