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

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 BH3/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 NaBH4- Cu(OAc)2 in EtOH at 78°C and purification with HPLC gave compound 12a in not, vert, similar5-10% 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 (not, vert, similar1%/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.