Measuring the effects of ketamine on mGluR5 using [ 18 F]FPEB and PET.

The metabotropic glutamate receptor 5 (mGluR5) is a promising treatment target for psychiatric disorders due to its modulatory effects on glutamate transmission. Using [ ¹¹ C]ABP688, we previously showed that the rapidly acting antidepressant ketamine decreases mGluR5 availability. The mGluR5 radioligand [ ¹⁸ F]FPEB offers key advantages over [ ¹¹ C]ABP688; however, its suitability for drug challenge studies is unknown. We evaluated whether [ ¹⁸ F]FPEB can be used to capture ketamine-induced effects on mGluR5. Seven healthy subjects participated in three [ ¹⁸ F]FPEB scans: a baseline, a same-day post-ketamine, and a 24-h post-ketamine scan. The outcome measure was V _T / f _P , obtained using a two-tissue compartment model and a metabolite-corrected arterial input function. Dissociative symptoms, heart rate and blood pressure increased following ketamine infusion. [ ¹⁸ F]FPEB V _T / f _P decreased by 9% across the cortex after ketamine infusion, with minimal difference between baseline and 24-h scans. Compared to our previous work using [ ¹¹ C]ABP688, the magnitude of the ketamine-induced change in mGluR5 was smaller using [ ¹⁸ F]FPEB; however, effect sizes were similar for the same-day post-ketamine vs. baseline scan (Cohen's d = 0.75 for [ ¹⁸ F]FPEB and 0.88 for [ ¹¹ C]ABP688). [ ¹⁸ F]FPEB is therefore able to capture some of the effects of ketamine on mGluR5, but [ ¹¹ C]ABP688 appears to be more suitable in drug challenge paradigms designed to probe glutamate transmission.