Development and Evaluation of Novel PET Tracers for Imaging Cannabinoid Receptor Type 2 in Brain

Abstract

The cannabinoid receptor type 2 (CB2) has a very low expression level in brain tissue under basal conditions, but it is up-regulated in diverse pathological conditions. Two promising lead structures from the literature, N-((3S,5S,7S)-adamantan-1-yl)-8-methoxy-4-oxo-1-pentyl-1,4-dihydroquinoline-3-carboxamide and 8-butoxy-N-(2-fluoro-2-phenylethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxamide -designated KD2 and KP23, respectively -were evaluated as potential PET ligands for imaging CB2. Both KD2 and KP23 were synthesized and labeled with carbon-11. In vitro autoradiographic studies on rodent spleen tissues showed that [(11)C]KD2 exhibits superior properties. A pilot study using [(11)C]KD2 on human post mortem ALS spinal cord slices indicated high CB2 expression level and specific binding, a very exciting finding if considering the future diagnostic application of CB2 ligands and their utility in therapy monitoring. In vivo blocking studies in rats with [(11)C]KD2 showed also high specific uptake in spleen tissue. Although the protein-bound fraction is relatively high, KD2 or KD2 derivatives could be very useful tools for the non-invasive investigation of CB2 levels under various neuroinflammatory conditions. SCS-DSM Award for best poster presentationAbstract: The cannabinoid receptor type 2 (CB2) has a very low expression level in brain tissue under basal conditions, but it is up-regulated in diverse pathological conditions. Tw o promising lead structures from the literature, N-((3S,5S,7S)-adamantan-1-yl)-8-methoxy-4-oxo-1-pentyl-1,4-dihydroquinoline-3-carboxamide and 8-butoxy-N-(2-fluoro-2-phenylethyl)-7-methoxy-2-oxo-1,2-dihydroquinoline-3-carboxamide -designated KD2 and KP23, respectively -were evaluated as potential PET ligands for imaging CB2. Both KD2 and KP23 were synthesized and labeled with carbon-11. In vitro autoradiographic studies on rodent spleen tissues showed that [ 11 C]KD2 exhibits superior properties. A pilot study using [ 11 C]KD2 on human post mortem ALS spinal cord slices indicated high CB2 expression level and specific binding, a very exciting finding if considering the future diagnostic application of CB2 ligands and their utility in therapy monitoring. In vivo blocking studies in rats with [ 11 C]KD2 showed also high specific uptake in spleen tissue. Although the protein-bound fraction is relatively high, KD2 or KD2 derivatives could be very useful tools for the non-invasive investigation of CB2 levels under various neuroinflammatory conditions.

Development of a High-Affinity PET Radioligand for Imaging Cannabinoid Subtype 2 Receptor

“…30−38 Molecular imaging with positron emission tomography (PET) of diseasespecific expression of CB 2 receptors in various disorders of the central nervous system like neuroinflammation, neurodegeneration, and glioma offers the potential of individualized diagnosis and therapeutic monitoring. 39 Recently, a substantial effort has been put into the development of radioligands for PET imaging of CB 2 receptors (for reviews, see refs 31, 40, and 41). Several radiolabeled CB 2 molecules have been developed with the most representative ones depicted in Figure 1.…”

“…CB 2 -selective ligands have gained increasing importance as therapeutic drugs for the diseases mentioned above, especially for the prevention of psychoactive side effects. − Molecular imaging with positron emission tomography (PET) of disease-specific expression of CB 2 receptors in various disorders of the central nervous system like neuroinflammation, neurodegeneration, and glioma offers the potential of individualized diagnosis and therapeutic monitoring …”

From adolescent to elder rats: Motivation for palatable food and cannabinoids receptors

“…The presence of CB2R in the brain has been widely shown (Van Sickle et al, 2005;Onaivi et al, 2006Onaivi et al, , 2008Navarrete et al, 2013;Slavik et al, 2014). Also, CB2R activation inhibits cocaine self-administration (Xi et al, 2011), while a contrasting finding is that the absence of CB2R as in the CB2RKO mice, prevents the development of CPP to nicotine (Navarrete et al, 2013).…”

Heterogeneity of Neuroinflammatory Responses in Amyotrophic Lateral Sclerosis: A Challenge or an Opportunity?

“…To date, [ 11 C]NE40 is the only one CB2 PET tracer tested in vivo in humans. Only two recently developed CB2r ligands, [ 11 C]KD2 and [ 18 F]3, have been tested in ALS, on human post mortem spinal cord samples, demonstrating high specificity for the affected CNS areas [127][128][129]. On the other hand, also P2X7r is being investigated for PET imaging of neuroinflammation, however, only few preclinical studies are available in the literature and they are limited to LPS-induced neuroinflammation mouse models [130].…”