[11C]Yohimbine

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 [¹¹C]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 [¹¹C]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. [¹¹C]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 [¹¹C]yohimbine can be used to evaluate acute variations in synaptic noradrenaline concentrations after pharmacological challenges.

Thirteen healthy humans underwent two [¹¹C]yohimbine 90-minute dynamic scans performed on a PET-MRI scanner. Seven had arterial blood sampling with metabolite assessment and plasmatic yohimbine free fraction evaluation at the first scan to have arterial input function and test appropriate kinetic modeling. The second scan was a simple retest for 6 subjects to evaluate the test-retest reproducibility. For the remaining 7 subjects the second scan was a challenge study with the administration of a single oral dose of 150 µg of clonidine 90 min before the PET scan. Parametric images of α2-ARs distribution volume ratios (DVR) were generated with two non-invasive models: Logan graphical analysis with Reference (LREF) and Simplified Reference Tissue Method (SRTM). Three reference regions (cerebellum white matter (CERWM), frontal white matter (FLWM), and corpus callosum (CC)) were tested.

We showed high test-retest reproducibility of DVR estimation with LREF and SRTM regardless of reference region (CC, CERWM, FLWM). The best fit was obtained with SRTM_CC (r²=0.94). Test-retest showed that the SRTM_CC is highly reproducible (mean ICC>0.7), with a slight bias (-1.8%), whereas SRTM_CERWM had lower bias (-0.1%), and excellent ICC (mean>0.8). Using SRTM_CC, regional changes have been observed after clonidine administration with a significant increase reported in the amygdala and striatum as well as in several posterior cortical areas as revealed with the voxel-based analysis.

The results add experimental support for the suitability of [¹¹C]yohimbine PET in the quantitative assessment of α2-ARs occupancy in vivo in the human brain. Trial registration EudraCT 2018-000380-82.