Identification and Preclinical Development of a 2,5,6-Trisubstituted Fluorinated Pyridine Derivative as a Radioligand for the Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors

Abstract

Despite the broad implications of the cannabinoid type 2 receptor (CB2) in neuroinflammatory processes, a suitable CB2-targeted probe is currently lacking in clinical routine. In this work, we synthesized 15 fluorinated pyridine derivatives and tested their binding affinities toward CB2 and CB1. With a sub-nanomolar affinity (K i for CB2) of 0.8 nM and a remarkable selectivity factor of >12,000 over CB1, RoSMA-18-d 6 exhibited outstanding in vitro performance characteristics and was radiofluorinated with an average radiochemical yield of 10.6 ± 3.8% (n = 16) and molar activities ranging from 52 to 65 GBq/μmol (radiochemical purity > 99%). [18F]­RoSMA-18-d 6 showed exceptional CB2 attributes as demonstrated by in vitro autoradiography, ex vivo biodistribution, and positron emission tomography (PET). Further, [18F]­RoSMA-18-d 6 was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [18F]­RoSMA-18-d 6 is a promising CB2 PET radioligand for clinical translation.

Detection of cannabinoid receptor type 2 in native cells and zebrafish with a highly potent, cell-permeable fluorescent probe

“…Accordingly, here we employ a drug-derived, reverse-design approach from a pharmacologically well-validated in vivo active compound class that would satisfy a number of desirable boundary conditions: affinity, potency and selectivity, chemical stability, water solubility and membrane permeability. 19,20 A ligand that meets these criteria is 1, [21][22][23] displaying picomolar selective binding affinity on human and mouse CB 2 R and full agonistic picomolar potency (Fig. 1B and ESI Table S1 †).…”

Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain

“…Further, labelled 2,3,5-oxodiazoles were prepared by Ahamed [ 60 ] and co-workers as derivatives of radioligands earlier reported by Teodoro [ 61 ] and co-workers and evaluated for their ability to detect CB2R in vivo. Recently, considerable progress was made by the discovery of the 11 C- and 18 F-labelled pyridine radioligands [ 11 C] RSR-056 and [ 18 F] 3 [ 62 , 63 ] and, most importantly, the deuterated analogue [ 18 F] RoSMA-18- d 6 , [ 64 ], which appears to be the most promising CB2R radioligand for PET imaging so far.…”

The Repertoire of Small-Molecule PET Probes for Neuroinflammation Imaging: Challenges and Opportunities beyond TSPO

“…To address this issue, the influence of structural modifications at position 6 of the pyridine ring was assessed, ultimately prompting the discovery of [ 18 F]48 ([ 18 F]RoSMA-18), a pyridine derivative with an outstanding target affinity (K i hCB2R = 0.7 nM) and selectivity (>12 000) over CB1R across different species. 76 Indeed, [ 18 F]RoSMA-18 showed excellent specificities for the CB2R-positive spleen tissue by in vitro autoradiography as well as by PET imaging and ex vivo biodistribution in rodents. Further, [ 18 F]RoSMA-18 was successfully employed to detect CB2R upregulation in human ALS spinal cord tissue.…”