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.

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The synthesis of 4‐substituted piperidine‐3‐carboxylates was achieved by conjugate addition of organomagnesium cuprates to N‐methyl and N‐tert‐butoxycarbonyl guvacine derivatives. Good to excellent yields were obtained with primary Grignard reagents containing alkyl, alkenyl, alkynyl, or masked aldehyde groups in a copper(I)‐trimethylsilylacetylide‐catalysed and chlorotrimethylsilane (TMSCl) mediated procedure.

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