Effect of 5-HT on binding of [¹¹C] WAY 100635 to 5-HT_1A receptors in rat brain, assessed using in vivo microdialysis and PET after fenfluramine

By using a combination of positron emission tomography (PET) and postmortem tissue dissection, the effect of increased endogenous serotonin on specific binding of [¹¹C]WAY 100635 to the 5-HT_1A receptor was investigated in rat brain in vivo. The binding studies were complemented by in vivo microdialysis to monitor 5-HT levels in similarly treated isoflurane-anaesthetised rats, with the dialysis probe locations corresponding to two of the tissues sampled for specific binding of the radioligand. Fenfluramine treatment (10 mg/kg i.p.) resulted in a ∼5-fold increase in extracellular 5-HT in medial prefrontal cortex and a ∼15-fold increase in lateral hippocampus, maximal at ∼40 min after injection. PET scan duration was either 60 or 90 min, beginning 30 min after fenfluramine injection. The specific binding of [¹¹C]WAY 100635 was reduced by 10-20% in hippocampus, which showed highest binding in control animals. Specific binding, however, was unaffected in both prefrontal cortex and midbrain raphe, each additional high binding regions. The minimal effects are consistent with a low baseline occupancy of the 5-HT_1A receptor by 5-HT in vivo, so that only a large change in endogenous agonist concentration will affect radioligand binding. This implies that utilisation of [¹¹C]WAY 100635 in human PET to quantify 5-HT_1A receptor expression can be extended to pathology where synaptic 5-HT levels are altered as a consequence of the disease state.