123I]AM281 single-photon emission computed tomography imaging of central cannabinoid CB 1 receptors before and after Δ 9-tetrahydrocannabinol therapy and whole-body scanning for assessment of radiation dose in tourette patients

Abstract

Background The cannabinoid CB 1 receptor agonist Δ 9-THC has been suggested for treatment of Tourette syndrome (TS). Based on animal studies, the CB 1 antagonist [ 123I]AM281 (N-(Morpholin-4-yl)-1-(2,4-dichlorophenyl)-5-(4-[ 123I]iodophenyl)-4-methyl-1H-pyrazole-3-carboxamide) has been proposed for single photon emission computed tomography (SPECT) in humans. Our aims were to 1) evaluate specific binding of [ 123I]AM281 to CB 1 receptors in TS patients and 2) assess radiation exposure associated with the use of AM281 labeled with 123I for SPECT and 124I for positron emission tomography. Methods We employed [ 123I]AM281 in six TS patients before and after Δ 9-THC treatment. Dynamic SPECT, plasma measurements (including metabolite analysis with thin layer chromatography), and whole-body imaging were performed. Regions of interest derived from magnetic resonance images were used to extract from SPECT uptake in an area with high CB 1 density (lentiform nuclei) and reference regions. Specific over nonspecific partition coefficients V 3′′ were calculated. Whole-body images were carried out for dosimetric analysis. Data obtained with [ 123I]AM281 were used to predict doses from [ 124I]AM281. Results Mean V 3′′ ranged from .19 to .31 and did not change significantly after Δ 9-THC treatment. Nevertheless, in the only patient with a marked clinical response, V 3′′ clearly declined. Thin layer chromatography revealed biexponential kinetics of tracer metabolism; about 60% remained nonmetabolized after 3 hours. Effective doses of .011 mSv/MBq for [ 123I]AM281 and .34 for [ 124I]AM281 were computed. Conclusions This study suggests that specific binding of [ 123I]AM281 to CB 1 receptors can be detected in patients using SPECT. Radiation exposure with [ 123I]AM281 is low; that with [ 124I]AM281 is higher but acceptable for single investigations.