Synthesis and Evaluation of Methylated Arylazepine Compounds for PET Imaging of 5-HT 2c Receptors
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Granda, Michael L.
Carlin, Stephen M.
Moseley, Christian K.
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CitationGranda, Michael L., Stephen M. Carlin, Christian K. Moseley, Ramesh Neelamegam, Joseph B. Mandeville, and Jacob M. Hooker. 2013. “Synthesis and Evaluation of Methylated Arylazepine Compounds for PET Imaging of 5-HT2cReceptors.” ACS Chemical Neuroscience 4 (2) (February 20): 261–265. doi:10.1021/cn300223d.
AbstractThe serotonin 5-HT2c receptor is implicated in a number of diseases including obesity, depression, anxiety, and schizophrenia. In order to ascribe the role of 5-HT2c in these diseases, a method for measuring 5-HT2c density and function in vivo, such as with positron emission tomography (PET), must be developed. Many high-affinity and relatively selective ligands exist for 5-HT2c but cannot be accessed with current radiosynthetic methods for use as PET radiotracers. We propose that N-methylation of an arylazepine moiety, a frequent structural feature in 5-HT2c ligands, may be a suitable method for producing new radiotracers for 5-HT2c. The impact of N-methylation has not been previously reported. For the agonists that we selected herein, N-methylation was found to increase affinity up to 8-fold without impairing selectivity. Compound 5, an N-methylated azetidine-derived arylazepine, was found to be brain penetrant and reached a brain/blood ratio of 2.05:1. However, our initial test compound was rapidly metabolized within 20 min of administration and exhibited high nonspecific binding. N-Methylation, with 16 ± 3% isolated radiochemical yield (decay corrected), is robust and may facilitate screening other 5-HT2c ligands as radiotracers for PET.
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