TY - JOUR
T1 - Synthesis and evaluation of methylated arylazepine compounds for PET imaging of 5-HT2c receptors
AU - Granda, Michael L.
AU - Carlin, Stephen M.
AU - Moseley, Christian K.
AU - Neelamegam, Ramesh
AU - Mandeville, Joseph B.
AU - Hooker, Jacob M.
PY - 2013/2/20
Y1 - 2013/2/20
N2 - 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-HT2cdensity 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.
AB - 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-HT2cdensity 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.
KW - 5-HT agonist
KW - PET imaging
KW - Serotonin
KW - carbon-11
UR - http://www.scopus.com/inward/record.url?scp=84874059598&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84874059598&partnerID=8YFLogxK
U2 - 10.1021/cn300223d
DO - 10.1021/cn300223d
M3 - Article
C2 - 23421677
AN - SCOPUS:84874059598
VL - 4
SP - 261
EP - 265
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 2
ER -