Abstract
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.
Highlights
The psychoactive effect of the well-known drug marijuana is caused by the active ingredient (−)-∆9-trans-tetrahydrocannabinol (THC), which abundantly occurs in the cannabis plant [1]
While the CB1R is associated with the central nervous system and is abundantly expressed in the brain, the CB2R is found in the spleen, tonsils and the thymus gland and modulates immune cell functions
We focus on the development and biological evaluation of a radiofluorinated compound belonging to the naphthyridin-2-one class, and we selected compound 5 (Scheme 1) due to the published high affinity and selectivity towards CB2R (Ki = 1.3 nM, SI > 700) and its favourable physicochemical properties for targeting the brain [34,65,66]
Summary
The psychoactive effect of the well-known drug marijuana is caused by the active ingredient (−)-∆9-trans-tetrahydrocannabinol (THC), which abundantly occurs in the cannabis plant [1]. The investigation of the mechanism through which THC manifests its biological activity led to the discovery of the endocannabinoid system. It comprises a class of transmembrane proteins that belongs to the superfamily of G-protein-coupled receptors; their endogenous ligands (endocannabinoids), such as anandamide (AEA) [2] and 2-arachidonoylglycerol (2-AG); the endocannabinoid-synthesising (diacylglycerol lipase N-acylphosphatidyl-ethanolamine phospholipase D) and -degrading enzymes (fatty acid amide hydrolase, monoacylglycerol lipase), as well as the endocannabinoid transporters [3,4]. The development of novel potent and selective CB2R ligands is supported by computer-based docking studies and accelerated by the recently reported crystal structure of the receptor [41]. The non-invasive imaging of CB2R with positron emission tomography (PET) is of great interest, as demonstrated by the large number of positron-emitting radioligands developed over the past years [42,43,44,45,46]
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