title: Synthesis and evaluation of methylated arylazepine compounds for PET imaging of 5-HT(2c) receptors.
abstract: The serotonin 5-HT(2c) receptor is implicated in a number of diseases including obesity, depression, anxiety, and schizophrenia. In order to ascribe the role of 5-HT(2c) in these diseases, a method for measuring 5-HT(2c )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-HT(2c) 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-HT(2c) ligands, may be a suitable method for producing new radiotracers for 5-HT(2c). 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-HT(2c) ligands as radiotracers for PET.
authors: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors: Michael L
authors: ML
authors: Granda
authors: Stephen M
authors: SM
authors: Carlin
authors: Christian K
authors: CK
authors: Moseley
authors: Ramesh
authors: R
authors: Neelamegam
authors: Joseph B
authors: JB
authors: Mandeville
authors: Jacob M
authors: JM
authors: Hooker
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging*; D002250:Carbon Radioisotopes / Q000378:metabolism; D008745:Methylation; D048530:Papio anubis; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000378:metabolism; D044405:Receptor, Serotonin, 5-HT2C / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000138:chemical synthesis* / Q000378:metabolism
chemical_list: D001381:Azepines; D002250:Carbon Radioisotopes; D019275:Radiopharmaceuticals; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists