Measuring the effects of ketamine on mGluR5 using [¹⁸F]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 [¹¹C]ABP688, we previously showed that the rapidly acting antidepressant ketamine decreases mGluR5 availability. The mGluR5 radioligand [¹⁸F]FPEB offers key advantages over [¹¹C]ABP688; however, its suitability for drug challenge studies is unknown. We evaluated whether [¹⁸F]FPEB can be used to capture ketamine-induced effects on mGluR5. Seven healthy subjects participated in three [¹⁸F]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. [¹⁸F]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 [¹¹C]ABP688, the magnitude of the ketamine-induced change in mGluR5 was smaller using [¹⁸F]FPEB; however, effect sizes were similar for the same-day post-ketamine vs. baseline scan (Cohen's d = 0.75 for [¹⁸F]FPEB and 0.88 for [¹¹C]ABP688). [¹⁸F]FPEB is therefore able to capture some of the effects of ketamine on mGluR5, but [¹¹C]ABP688 appears to be more suitable in drug challenge paradigms designed to probe glutamate transmission.