Synthesis of N, N-dimethyl-2-(2-amino-4-[ 18F]fluorophenylthio)benzylamine as a serotonin transporter imaging agent

Abstract

Two 403U76 analogs, N, N-dimethyl-2-(2-nitro-4-bromophenylthio)benzylamine ( 4) and N, N-dimethyl-2-(2,4-dinitrophenylthio)benzylamine ( 8) were prepared in multi-steps synthesis as precursors for the synthesis of a new serotonin transporter imaging agent, N, N-dimethyl-2-(2-amino-4-[ 18F]fluorophenylthio)benzylamine ( 12a). Reaction of 2,5-dibromonitrobenzene ( 1) with 2-thio- N, N-dimethylbenzamide gave N N-dimethyl-2-(2-nitro-4-bromophenylthio)benzamide ( 3). N, N-Dimethyl-2-(2,4-dinitrophenylthio)benzamide ( 6) was synthesized similarly from the reaction of 2-bromo-1,5-dinitrobenzene ( 2) with 2-thio- N, N-dimethylbenzamide. Reduction of 3 and 6 with BH 3/THF gave benzylamines 4 and 8 along with their amine boranes 5 and 7. Nucleophilic substitution of 4 or 8 with K[ 18F]/Kryptofix 2.2.2 in DMSO at 120°C followed by reduction with NaBH 4- Cu(OAc) 2 in EtOH at 78°C and purification with HPLC gave compound 12a in ∼5-10% yield in a synthesis time of 150 min from EOB. A preliminary biodistribution study in rats showed that the uptake of compound 12a in rat brain was high (∼1%/g) and the ratio of the uptake of compound 12a in hypothalamus (a serotonin transporter-rich area) and cerebellum (a serotonin-transporter-devoid area) was 6/1 at 1 h post-injection. These results suggest that compound 12a may be a potential new serotonin transporter PET imaging agent.