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Title: Validation of PET radioligands for visualisation of the cannabinoid type 2 receptor in a rat model with local cerebral CB2R expression
Authors: Evens, Nele
Vandeputte, Caroline
Debyser, Zeger
Baekelandt, Veerle
Verbruggen, Alfons
Van Laere, Koen
Bormans, Guy #
Issue Date: Oct-2009
Conference: Congress of the European Association of Nuclear Medicine location:Barcelona, Spain date:10-14 october 2009
Abstract: Aim
The type 2 cannabinoid receptor (CB2R) is part of the endocannabinoid system and is predominantly expressed in cells related to the immune system. In contrast to the type 1 cannabinoid receptor, there is no significant expression of the CB2R in the cerebrum in control conditions. However, elevated CB2R expression is present in activated microglia, near senile amyloid plaques in Alzheimer patients and plaques of demyelination in multiple sclerosis patients.
We reported three CB2R PET tracers, (2,3-dichloro-phenyl)-[5-[11C]methoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]methanone (1), (2,3-dichloro-phenyl)-[5-[18F]fluoroethoxy-2-methyl-3-(2-morpholin-4-yl-ethyl)-indol-1-yl]methanone (2) and 7-[11C]methoxy-2-oxo-8-butyloxy-1,2-dihydroquinoline-3-carboxylic acid cyclohexylamide (3), all showing high brain uptake and good in vitro affinity for human CB2R (hCB2R). Moreover, 3 shows in vivo CB2R binding in mouse and rat spleen. Here, we extended evaluation of 1, 2 and 3 in a rat model with local cerebral CB2R expression.
Materials and methods
An adeno-associated viral vector (AAV) encoding human CB2R (hCB2R) with a point mutation (Asp80Asn) or CB2(D80N) was stereotactically injected in the right striatum of normal rats, while a control vector was injected in the left striatum.
Small animal PET imaging was performed using a FOCUS 220 tomograph (Siemens/Concorde Microsystems, Knoxville, TN) on different time points after vector injection and with three different tracers. Specific CB2 receptor binding was confirmed by ‘chasing’ studies with ‘cold’ 1 20 minutes after tracer injection.

Results
Uptake in right striatum (hCB2R vector) is persistently higher than uptake in left striatum (control vector) for all tracers (approximately 1.7 times higher for 1 and 2 and 3 times higher for 3 at 2000 s p.i.). The uptake in the left striatum is comparable to the uptake in the cerebellum (control level). When the animal is treated with ‘cold’ 1 20 minutes after tracer injection (of 1, 2 or 3), the activity in the right striatum drops to the activity level in the left striatum showing inhibition of tracer binding and thereby confirming specific and reversible (hCB2R) binding.

Conclusions
All tested tracers show in vivo hCB2R binding in a rat model with local CB2R expression and are promising candidates for in vivo CB2 imaging with PET.
Publication status: submitted
KU Leuven publication type: IMa
Appears in Collections:Molecular Virology and Gene Therapy
Radiopharmacy
Nuclear Medicine & Molecular Imaging
Research Group for Neurobiology and Gene Therapy
# (joint) last author

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