Imaging evaluation of 5HT2C agonists, [(11)C]WAY-163909 and [(11)C]vabicaserin, formed by Pictet-Spengler cyclization.
The serotonin subtype 2C (5HT2C) receptor is an emerging and promising drug target to treat several disorders of the human central nervous system. In this current report, two potent and selective 5HT2C full agonists, WAY-163909 (2) and vabicaserin (3), were radiolabeled with carbon-11 via Pictet-Spengler cyclization with [(11)C]formaldehyde and used in positron emission tomography (PET) imaging. Reaction conditions were optimized to exclude the major source of isotope dilution caused by the previously unknown breakdown of N,N-dimethylformamide (DMF) to formaldehyde at high temperature under mildly acid conditions. In vivo PET imaging was utilized to evaluate the pharmacokinetics and distribution of the carbon-11 labeled 5HT2C agonists. Both radiolabeled molecules exhibit high blood-brain barrier (BBB) penetration and nonspecific binding, which was unaltered by preadministration of the unlabeled agonist. Our work demonstrates that Pictet-Spengler cyclization can be used to label drugs with carbon-11 to study their pharmacokinetics and for evaluation as PET radiotracers.
Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School , Charlestown, Massachusetts 02129, United States.
Ramesh
R
Neelamegam
Tim
T
Hellenbrand
Frederick A
FA
Schroeder
Changning
C
Wang
Jacob M
JM
Hooker
D001381:Azepines / Q000737:chemistry*; D002250:Carbon Radioisotopes / Q000737:chemistry*; D003500:Cyclization; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry*; D007211:Indoles / Q000737:chemistry*; D049268:Positron-Emission Tomography; D017366:Serotonin Receptor Agonists / Q000737:chemistry*
C501656:1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta(b)(1,4)diazepino(6,7,1hj)indole; D001381:Azepines; D002250:Carbon Radioisotopes; D006576:Heterocyclic Compounds, 4 or More Rings; D007211:Indoles; D017366:Serotonin Receptor Agonists; C556517:vabicaserin