@inproceedings{oai:repo.qst.go.jp:00086452,
 author = {Rong, Jian and Tomoteru, Yamasaki and Zhao, Chunyu and Chen, Jiahui and Zhiwei, Xiao and Li, Yinlong and Lee Collier, Thomas and Zhang, Ming-Rong and Liang, Steven and Tomoteru, Yamasaki and Zhang, Ming-Rong},
 book = {Nuclear Medicine and Biology},
 month = {Jun},
 note = {Objectives: The orexin network mainly relies on two G protein-coupled receptors, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R), and two neuropeptides, orexin-A (a 33 amino acid peptide) and orexin-B (a 28 amino acid peptide). Orexin-A is a non-selective neuropeptide binding both OX1R and OX2R with similar affinities, while orexin-B has a much higher selectivity towards OX2R against OX1R (> 10 fold). It has been found that OX2R plays a key role in motivation, arousal and sleep-wake regulation. Several OX2R ligands have been developed for OX2R PET imaging, but highly specific PET probes are still lacking. Herein we report [11C]1 and [11C]2 as novel and potential PET ligands for orexin 2 receptor imaging.
Methods: Compounds 1 and 2 were synthesized according to patent literature WO2004033418. The phenolic precursors were prepared from demethylation of compounds 1 and 2. The radiosynthesis of [11C]1 and [11C]2 were conducted by 11C-methylation of phenolic precursors precursors with [11C]CH3I and Cs2CO3 as the base in DMF at 80 oC for 5 min. The in vitro autoradiography studies on Sprague Dawley rat brain slices was performed.
Results: Compounds 1 was prepared starting from 2-methoxyaniline, which was treated with 3-methylpyridine-2-sulfonyl chloride to obtain N-(2-methoxyphenyl)-3-methylpyridine-2-sulfonamide in 21% yield. The resulting compound was coupled with methyl 2-bromoacetate in 45% yield and then hydrolyzed with NaOH to form carboxylic acid, which was coupled to N-benzylethanamine in the presence of HATU providing compound 1 in 2% overall yield over four steps. Compounds 2 was synthesized in a similar pathway and achieved in 20% overall yield over four steps. The phenolic precursors were prepared from demethylation of compounds 1 and 2 in 41% and 45% yields, respectively. The PET ligands [11C]1 and [11C]2 were prepared via reactions with [11C]CH3I and both achieved in more than 10% radiochemical yields (decay corrected). The radiochemical purities of these tracers were greater than 99%, and both [11C]1 and [11C]2 were stable in saline in 90 min. In in vitro autoradiography studies with [11C]1 and [11C]2, high radioactivity accumulation was observed in the hippocampus, and cortex. In blocking studies, EMPA (10 μM) rendered diminished radioactivity in OX2R-rich brain regions.
Conclusion: We have developed two novel PET ligand [11C]1 and [11C]2 for imaging OX2R. The PET ligands [11C]1 and [11C]2 were both prepared in more than 10% radiochemical yield (decay corrected). High radioactivity accumulation was observed in the hippocampus, and cortex in in vitro autoradiography studies with [11C]1 and [11C]2. These tracers will be evaluated in the PET imaging study for OX2R in rodents and the results will be reported in due course.},
 publisher = {Elsevier Ltd.},
 title = {Synthesis and Evaluation of Novel PET Ligands for Imaging Orexin2 receptor (OX2R)},
 year = {2022}
}