Synthesis and Evaluation of Methylated Arylazepine Compounds for PET Imaging of 5-HT 2c Receptors
View/ Open
Hooker_SynthesisEvaluationMethylated.pdf (1.698Mb)
Access Status
Full text of the requested work is not available in DASH at this time ("restricted access"). For more information on restricted deposits, see our FAQ.Author
Granda, Michael L.
Carlin, Stephen M.
Moseley, Christian K.
Published Version
https://doi.org/10.1021/cn300223dMetadata
Show full item recordCitation
Granda, 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.Abstract
The 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.Citable link to this page
http://nrs.harvard.edu/urn-3:HUL.InstRepos:33490453
Collections
- FAS Scholarly Articles [18299]
Contact administrator regarding this item (to report mistakes or request changes)