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The development of cannabinoid receptor type 2 (CB2R) PET radioligands has been intensively explored due to the pronounced CB2R upregulation under various pathological conditions. Herein, we report on the synthesis of a series of CB2R affine fluorinated indole-2-carboxamide ligands. Compound RM365 was selected for PET radiotracer development due to its high CB2R affinity ( K i = 2.1 nM) and selectivity over CB1R (factor > 300). Preliminary in vitro evaluation of [ 18 F]RM365 indicated species differences in the binding to CB2R ( K D of 2.32 nM for the hCB2R vs K D > 10,000 nM for the rCB2R). Metabolism studies in mice revealed a high in vivo stability of [ 18 F]RM365. PET imaging in a rat model of local hCB2R(D80N) overexpression in the brain demonstrates the ability of [ 18 F]RM365 to reach and selectively label the hCB2R(D80N) with a high signal-to-background ratio. Thus, [ 18 F]RM365 is a very promising PET radioligand for the imaging of upregulated hCB2R expression under pathological conditions.

The development of cannabinoid receptor type 2 (CB 2 R) radioligands for positron emission tomography (PET) imaging was intensively explored. To overcome the low metabolic stability and simultaneously increase the binding affinity of known CB 2 R 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 CB 2 R ligands. All tested compounds showed low nanomolar CB 2 R affinity, with ( Z )- N -[3-(4-fluorobutyl)-4,5-dimethylthiazole-2(3 H )-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 CB 2 R ligands and gaining access to a new class of high-affinity CB 2 R ligands, while the in vivo pharmacology still needs to be addressed.

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 18 F-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 (CB2R K i = 0.6 nM; CB1R K i /CB2R K 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.

Cannabinoid type 2 receptors (CB 2 receptors) are involved in various pathological processes, and the visualization of their in vivo availability with positron emission tomography (PET) is of high interest. The study focuses on the introduction of fluorine into the structure of the highly affine and selective CB 2 receptor ligand N -(adamantan-1-yl)-5-ethyl-2-methyl-1-phenyl-1 H -imidazole-4-carboxamide ( 5 ). A novel series of compounds was developed by modifying (i) the adamantane-3-position, (ii) the imidazole- N -phenyl ring, and (iii) the imidazole-2-position, and the impact on the CB 2 binding affinity and selectivity toward cannabinoid type 1 receptors (CB 1 ) was evaluated. This study identified compound 15 as one of the most potent ( K i (CB 2 ) = 0.29 nM) and selective (CB 1 /CB 2 > 10000) CB 2 receptor ligands discovered so far, eligible for the development of an 18 F-labeled PET radiotracer.

Cannabinoid receptors type 2 (CB2) represent a target with increasing importance for neuroimaging due to its upregulation under various pathological conditions. Encouraged by preliminary results obtained with [(11)C](Z)-N-(3-(2-methoxyethyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethyl-cyclopropanecarboxamide ([(11)C]A-836339, [(11)C]1) in a mouse model of acute neuroinflammation (induced by lipopolysaccharide, LPS), we designed a library of fluorinated analogues aiming for an [(18)F]-labeled radiotracer with improved CB2 binding affinity and selectivity. Compound (Z)-N-(3-(4-fluorobutyl)-4,5-dimethylthiazol-2(3H)-ylidene)-2,2,3,3-tetramethyl-cyclopropanecarboxamide (29) was selected as the ligand with the highest CB2 affinity (Ki = 0.39 nM) and selectivity over those of CB1 (factor of 1000). [(18)F]29 was prepared starting from the bromo precursor (53). Specific binding was shown in vitro, whereas fast metabolism was observed in vivo in CD-1 mice. Animal PET revealed a brain uptake comparable to that of [(11)C]1. In the LPS-treated mice, a 20-30% higher uptake in brain was found in comparison to that in nontreated mice (n = 3, P < 0.05).