Abstracts

Rationale: The cannabinoid CB₁ receptor is one of the most abundant G protein-coupled receptors in the brain¹. Animal models have demonstrated alterations in CB₁ receptor availability in response to seizures. Cannabinoid agonists can have a marked anti-seizure effect in some patients². However, in vivo human evidence of cannabinoid receptor alterations in epilepsy is lacking. MePPEP is a novel CB₁ inverse agonist that has been labelled with ¹¹C for use in positron emission tomography (PET). Here we compared post-ictal binding of [¹¹C]MePPEP in two patients to that of controls. Methods: [¹¹C]MePPEP PET scans were performed in fourteen healthy controls (10 males, mean age 31 years; range 20-65 years) and in two patients (both males, age 29 and 37) with focal epilepsy within two days following a spontaneous seizure presumed to arise either in the temporal or frontal neocortex. All subjects had a 90-minute dynamic PET scan on a Siemens/ECAT 962 scanner, each after intravenous injection of approximately 370MBq (mean: 360MBq, range 316-385MBq) of [¹¹C]MePPEP. Data were motion-corrected with a frame-to-frame co-registration method and spatially aligned with T1-weighted structural 3D images³ in all controls. Volumes-of-distribution (V_T) were quantified using arterial input functions (IFs) in anatomically defined selected areas⁴. We calculated the global intensities (GI) in all controls and chose hippocampus and inferior frontal gyrus (IFG) as regions-of-interest (ROI) for quantifying V_T. Finally, we compared the uptake of [¹¹C]MePPEP in patients with that of controls using Statistical Parametric Mapping (SPM). Results: Mean GI of summed 0-90 minute (ADD) images in controls was 1.31 (range 0.8-2.1). V_Ts were generated from three-tissue two-compartment models in both ROIs. Mean V_T value for hippocampus was 17.4 (range 2-6) and for IFG was 7.8 (range 2-16). Both patients showed upregulation of [¹¹C]MePPEP fixation in the presumed epileptogenic lobe. This was seen on both visual inspection of ADDs and on their preliminary SPM analysis (Figure 1). Conclusions: Our preliminary in vivo findings support a role of G-protein coupled CB₁ receptor in the modulation of seizure activity in humans, and open opportunities for a range of applications for [¹¹C]MePPEP PET as a tool in the presurgical investigation⁵. These results require further validation in a larger dataset of paired inter-ictal and post-ictal studies with data quantified using compartmental models⁶ and semiquantitative analysis using SPM. References: ¹Yasuno F et al. Neuropsychopharmacology 2008;33:259-69. ²Mortati K et al. Rev Neurol Dis 2007;4(2):103-6. ³Hammers A et al. Neuroimage 2007;38:82-94. ⁴Heckemann RA et al. Neuroimage 2006;33:115-26. ⁵Hammers A et al. Brain 2007;130:1009-16. ⁶Terry GE et al. Neuroimage 2009;48:362-370.