Combined In Vivo Microdialysis and PET Studies to Validate [(11)C]Yohimbine Binding as a Marker of Noradrenaline Release

The noradrenaline system attracts attention for its role in mood disorders and neurodegenerative diseases but the lack of well-validated methods impairs our understanding when assessing its function and release in vivo. This study combines simultaneous positron emission tomography (PET) and microdialysis to explore if [(11)C]yohimbine, a selective antagonist radioligand of the α2 adrenoceptors, may be used to assess in vivo changes in synaptic noradrenaline during acute pharmacological challenges. Anesthetised Göttingen minipigs were positioned in a head holder in a PET/CT device. Microdialysis probes were placed in the thalamus, striatum and cortex and dialysis samples were collected every 10 min. Three 90 min [(11)C]yohimbine scans were acquired: at baseline and at two timepoints after the administration of amphetamine (1–10 mg/kg), a non-specific releaser of dopamine and noradrenaline, or nisoxetine (1 mg/kg), a specific noradrenaline transporter inhibitor. [(11)C]yohimbine volumes of distribution (V(T)) were obtained using the Logan kinetic model. Both challenges induced a significant decrease in yohimbine V(T), with time courses reflecting their different mechanisms of action. Dialysis samples revealed a significant increase in noradrenaline extracellular concentrations after challenge and an inverse correlation with changes in yohimbine V(T). These data suggest that [(11)C]yohimbine can be used to evaluate acute variations in synaptic noradrenaline concentrations after pharmacological challenges.