Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[18F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([18F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [18F]LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.
The cannabinoid receptor type 2 (CB2R)
is an attractive target
for the diagnosis and therapy of neurodegenerative diseases and cancer.
In this study, we aimed at the development of a novel 18F-labeled radioligand starting from the structure of the known naphthyrid-2-one
CB2R ligands. Compound 28 (LU13) was identified
with the highest binding affinity and selectivity versus CB1R (CB2RK
i = 0.6 nM; CB1RK
i/CB2RK
i > 1000) and was selected for
radiolabeling with fluorine-18 and biological characterization. The
new radioligand [
18
F]LU13 showed high CB2R affinity in vitro as well as high metabolic stability
in vivo. PET imaging with [
18
F]LU13 in a rat model of vector-based/-related hCB2R
overexpression in the striatum revealed a high signal-to-background
ratio. Thus, [
18
F]LU13 is a novel and highly promising PET radioligand for the imaging
of upregulated CB2R expression under pathological conditions in the
brain.
The development of
cannabinoid receptor type 2 (CB2R)
radioligands for positron emission tomography (PET) imaging was intensively
explored. To overcome the low metabolic stability and simultaneously
increase the binding affinity of known CB2R radioligands,
a carborane moiety was used as a bioisostere. Here we report the synthesis
and characterization of carborane-based 1,8-naphthyridinones and thiazoles
as novel CB2R ligands. All tested compounds showed low
nanomolar CB2R affinity, with (Z)-N-[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3H)-ylidene]-(1,7-dicarba-closo-dodecaboranyl)-carboxamide
(LUZ5) exhibiting the highest affinity (0.8 nM). Compound [
18
F]LUZ5-d
8
was obtained with an automated radiosynthesizer
in high radiochemical yield and purity. In vivo evaluation
revealed the improved metabolic stability of [
18
F]LUZ5-d
8
compared to that of [
18
F]JHU94620. PET experiments in rats revealed high uptake
in spleen and low uptake in brain. Thus, the introduction of a carborane
moiety is an appropriate tool for modifying literature-known CB2R ligands and gaining access to a new class of high-affinity
CB2R ligands, while the in vivo pharmacology
still needs to be addressed.
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