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The cannabinoid type 2 receptor (CB2) has been implicated in a variety of central and peripheral inflammatory diseases, prompting significant interest in the development of CB2-targeted diagnostic and therapeutic agents. A validated positron emission tomography (PET) radioligand for imaging CB2 in the living human brain as well as in peripheral tissues is currently lacking. As part of our research program, we have recently identified the trisubstituted pyridine, [ 18 F]RoSMA-18-d 6 , which proved to be highly suitable for in vitro and in vivo mapping of CB2 in rodents. The aim of this study was to assess the performance characteristics of [ 18 F]RoSMA-18-d 6 in nonhuman primates (NHPs) to pave the way for clinical translation. [ 18 F]RoSMA-18-d 6 was synthesized from the respective tosylate precursor according to previously reported procedures. In vitro autoradiograms with NHP spleen tissue sections revealed a high binding of [ 18 F]RoSMA-18-d 6 to the CB2-rich NHP spleen, which was significantly blocked by coincubation with the commercially available CB2 ligand, GW405833 (10 μM). In contrast, no specific binding was observed by in vitro autoradiography with NHP brain sections, which was in agreement with the notion of a CB2-deficient healthy mammalian brain. In vitro findings were corroborated by PET imaging experiments in NHPs, where [ 18 F]RoSMA-18-d 6 uptake in the spleen was dose-dependently attenuated with 1 and 5 mg/kg GW405833, while no specific brain signal was observed. Remarkably, we observed tracer uptake and retention in the NHP spinal cord, which was reduced by GW405833 blockade, pointing toward a potential utility of [ 18 F]RoSMA-18-d 6 in probing CB2-expressing cells in the bone marrow. If these observations are substantiated in NHP models of enhanced leukocyte proliferation in the bone marrow, [ 18 F]RoSMA-18-d 6 may serve as a valuable marker for hematopoietic activity in various pathologies. In conclusion, [ 18 F]RoSMA-18-d 6 proved to be a suitable PET radioligand for imaging CB2 in NHPs, supporting its translation to humans.

Monoacylglycerol lipase (MAGL) is one of the key enzymes in the endocannabinoid system. Inhibition of MAGL has been proposed as an attractive approach for the treatment of various diseases. In this study, we designed and successfully synthesized two series of piperazinyl pyrrolidin-2-one derivatives as novel reversible MAGL inhibitors. ( R )-[ 18 F] 13 was identified through the preliminary evaluation of two carbon-11-labeled racemic structures [ 11 C] 11 and [ 11 C] 16 . In dynamic positron-emission tomography (PET) scans, ( R )-[ 18 F] 13 showed a heterogeneous distribution and matched the MAGL expression pattern in the mouse brain. High brain uptake and brain-to-blood ratio were achieved by ( R )-[ 18 F] 13 in comparison with previously reported reversible MAGL PET radiotracers. Target occupancy studies with a therapeutic MAGL inhibitor revealed a dose-dependent reduction of ( R )-[ 18 F] 13 accumulation in the mouse brain. These findings indicate that ( R )-[ 18 F] 13 ([ 18 F]YH149) is a highly promising PET probe for visualizing MAGL non-invasively in vivo and holds great potential to support drug development.

Neuroinflammation is an adaptive response of the central nervous system to diverse potentially injurious stimuli, which is closely associated with neurodegeneration and typically characterized by activation of microglia and astrocytes. As a noninvasive and translational molecular imaging tool, positron emission tomography (PET) could provide a better understanding of neuroinflammation and its role in neurodegenerative diseases. Ligands to translator protein (TSPO), a putative marker of neuroinflammation, have been the most commonly studied in this context, but they suffer from serious limitations. Herein we present a repertoire of different structural chemotypes and novel PET ligand design for classical and emerging neuroinflammatory targets beyond TSPO. We believe that this Perspective will support multidisciplinary collaborations in academic and industrial institutions working on neuroinflammation and facilitate the progress of neuroinflammation PET probe development for clinical use.

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%). [ 18 F]RoSMA-18- d 6 showed exceptional CB2 attributes as demonstrated by in vitro autoradiography, ex vivo biodistribution, and positron emission tomography (PET). Further, [ 18 F]RoSMA-18- d 6 was used to detect CB2 upregulation on postmortem human ALS spinal cord tissues. Overall, these results suggest that [ 18 F]RoSMA-18- d 6 is a promising CB2 PET radioligand for clinical translation.

The cannabinoid type 2 (CB2) receptor has emerged as a valuable target for therapy and imaging of immune-mediated pathologies. With the aim to find a suitable radiofluorinated analogue of the previously reported CB2 positron emission tomography (PET) radioligand [ 11 C]RSR-056, 38 fluorinated derivatives were synthesized and tested by in vitro binding assays. With a K i (hCB2) of 6 nM and a selectivity factor of nearly 700 over cannabinoid type 1 receptors, target compound 3 exhibited optimal in vitro properties and was selected for evaluation as a PET radioligand. [ 18 F] 3 was obtained in an average radiochemical yield of 11 ± 4% and molar activities between 33 and 114 GBq/μmol. Specific binding of [ 18 F] 3 to CB2 was demonstrated by in vitro autoradiography and in vivo PET experiments using the CB2 ligand GW-405 833. Metabolite analysis revealed only intact [ 18 F] 3 in the rat brain. [ 18 F] 3 detected CB2 upregulation in human amyotrophic lateral sclerosis spinal cord tissue and may thus become a candidate for diagnostic use in humans.