Imaging of central cannabinoid CB1 receptors, a potential target for therapeutic agents in movement disorders

For several movement disorders a relevance of the cannabinoid system – in the pathophysiology and as a potential target of treatment – has been suggested. With respect to Huntington's disease, the early loss of CB₁ receptors has been related to the hyperkinesias, which are typical for the earliest phases of disease – and cannabinoids have been shown to protect cells against huntingtin-induced cell death. In Parkinson's disease, it has been suggested, that compounds affecting the CB₁ receptor alleviate levodopa induced dyskinesia via a modulation of GABAergic transmission in the basal ganglia. Furthermore, antidystonic effects of cannabinoids have been demonstrated in animal model and occasionally been communicated in clinical case reports. Finally, in Tourette syndrome, a significant reduction of tics due to delta-9-Tetrahydrocannabinol (THC) therapy has been found in a randomized, double-blind, placebo-controlled study. In the context of treatment of movement disorders with CB₁ receptor affine substances, in vivo receptor imaging could in principle provide unique information – regarding receptor status before therapy, degree of receptor occupation due to therapy and neuroprotective effects during follow up. So far, three different classes of compounds have been explored for their potential usefulness for CB₁ receptor imaging: classical cannabinoids, aminoalkylindoles and pyrazole derivatives. With a radioligand belonging to the last mentioned class – I-123-AM281– and SPECT (single-photon emission computed tomography) imaging the most promising results have been obtained so far. We employed this radioligand in six Tourette patients before and after treatment with THC. At baseline a specific to non-specific partition coefficient V₃ ^'' of 0.30±0.11 was measured for the lentiform nuclei during equilibrium. A distinct reduction of V₃ ^'' after THC was exclusively found in the only patient with clear clinical response. Nevertheless, to improve the limited contrast between specific and non-specific tracer binding, the development of less lipophilic ligands labelled with nuclides enabling PET (positron emission tomography) imaging would be worthwhile.