Imaging Evaluation of 5HT_2C Agonists, [¹¹C]WAY-163909 and [¹¹C]Vabicaserin, Formed by Pictet–Spengler Cyclization

Abstract

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 [11C]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.

Effects of the serotonin 2C receptor agonist WAY163909 on the abuse-related effects and mesolimbic dopamine neurochemistry induced by abused stimulants in rhesus monkeys

“…The aim of the present study, therefore, was to evaluate the effects of the highly selective serotonin 5-HT 2C receptor agonist WAY163909 (Dunlop et al 2005; Neelamegam et al 2014) on the behavioral neuropharmacology of cocaine and methamphetamine in rhesus monkeys. Studies have shown that WAY163909 exhibits excellent binding affinity ( K i of ∼10 nM) and functional selectivity for the human 5-HT 2C receptor (Dunlop et al 2005), being one of the most selective agents identified to date compared with other compounds reported in the literature, including Ro 60-0175 (Martin et al, 1998) and novel compounds such as lorcaserin (Thomsen et al, 2008) and vabicaserin (SCA-136) (Dunlop et al, 2011).…”

Metal‐Free Annulation Cascades of 1,7‐Enynes Using Di‐tert‐butyl Peroxide as the Methyl Source towards the Synthesis of Polyheterocyclic Scaffolds

“…Polyheterocyclic scaffold synthesis has attracted ongoing interest due to its application in drug discovery and material sciences . For example, Herbertenolide possesses anti‐tumor activity in vivo against KREBS II ascetic tumor and cytotoxicity in vitro against HTC hepatoma cells (Figure ) . As a result, much effort has been devoted towards constructing polyheterocyclic skeletons .…”

PET Tracers for Serotonin Receptors and Their Applications

“…There are several attempts recently made for the development of 5-HT 2C R PET tracers with limited success. These include a low affinity azetidine analogue of pyrimidoazepine, a 5-HT 2C agonist (K i = 75 nM) and antagonists WAY-163909 (K i = 10 nM) and vabicaserin (K i = 3 nM) [124, 125]. The radiosynthesis of [ 11 C]pyrimidoazepine has been achieved via [ 11 C]methylation using [ 11 C]CH 3 I, whereas the antagonist ligands were synthesized via a novel C-11 Pictet-Spengler cyclization with [ 11 C]CH 2 O ([124, 125].…”