Decreased in vivo availability of the cannabinoid type 2 receptor in Alzheimer’s disease

Abstract

Purpose

The cannabinoid type 2 receptor (CB₂R) is expressed by immune cells such as monocytes and macrophages. In the brain, CB₂R is primarily found on microglia. CB₂R upregulation has been reported in animal models of Alzheimer's disease, with a preferential localization near amyloid beta (Aβ) plaques, and in patients post mortem. We performed in vivo brain imaging and kinetic modelling of the CB₂R tracer [¹¹C]NE40 in healthy controls (HC) and in patients with Alzheimer's disease (AD) to investigate whether higher CB₂R availability regionally colocalized to Aβ deposits is present in vivo.

Methods

Dynamic 90-min [¹¹C]NE40 PET scans were performed in eight HC and nine AD patients with full kinetic modelling using arterial sampling and metabolite correction and partial volume correction. All AD patients received a static [¹¹C]PIB scan 40 min after injection. In four HC, a retest scan with [¹¹C]NE40 PET was performed within 9 weeks to investigate test–retest characteristics.

Results

[¹¹C]NE40 was metabolized quickly leading to 50 % of intact tracer 20 min after injection and 20 % at 90 min. A two-tissue kinetic model fitted most of the time–activity curves best; both binding potential (BP_ND) and distribution volume (V _T) parameters could be used. Brain uptake was generally low with an average K ₁ value of 0.07 ml/min/ml tissue. V _T and BP_ND were in the range of 0.7 – 1.8 and 0.6 – 1.6, respectively. Test values in HC were about 30 % for V _T and BP_ND. AD patients showed overall significantly lower CB₂R binding. No relationship was found between regional or global amyloid load and CB₂R availability.

Conclusion

Kinetic modelling of [¹¹C]NE40 is possible with a two-tissue reversible model. In contrast to preclinical and post-mortem data, [¹¹C]NE40 PET shows lower CB₂R availability in vivo in AD patients, with no relationship to Aβ plaques. A possible explanation for these findings is that [¹¹C]NE40 binds to CB₂R with lower affinity and/or selectivity than to CB₁R.

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