Serotonin Transporter Imaging Agent Research Articles

Synthesis and evaluation of N, N-dimethyl-2-(2-amino-5-[ 18F]fluorophenylthio)benzylamine (5-[ 18F]-ADAM) as a serotonin transporter imaging agent

The synthesis and evaluation of a new serotonin transporter (SERT) imaging agent, N, N-dimethyl-2-(2-amino-5-[ 18F]fluorophenylthio)benzylamine (5-[ 18F]-ADAM) is reported. Nucleophilic substitution of N, N-dimethyl-2-(2-nitro-5-bromophenylthio)benzylamine with K[ 18F]/Kryptofix 2.2.2 in DMSO at 125°C followed by reduction with NaBH 4–Cu(OAc) 2 in EtOH at 78°C and purification with HPLC produces the desired compound with an unoptimized yield of ∼5–10% in a synthesis time of 150 min from EOB. The biodistribution of 5-[ 18F]-ADAM in rats showed a high initial uptake and relatively rapid clearance in the brain (3.221±0.762, 0.440±0.059, 0.160±0.035 and 0.028±0.003% injected dose/organ at 2, 30, 60 and 120 min after I.V. injection, respectively) with the specific binding peaking at 1 h postinjection (hypothalamus/cerebellum and hippocampus/cerebellum were 2.97 and 3.59, respectively). The initial uptake in blood, lung, kidney and heart were also high, but it cleared rapidly. The radioactivity in the femur increased with time for 5-[ 18F]-ADAM indicating that in vivo defluorination may occur. Metabolism studies in rats showed that 5-[ 18F]-ADAM was not metabolized in rat brain, but was metabolized rapidly in the blood. Blocking experiments showed that there were significant decreases in the uptake of 5-[ 18F]-ADAM in the brain regions (hypothalamus, hippocampus and striatum) where SERT concentrations are high when rats were pretreated with (+)McN 5652 (2 mg/kg, 5 min prior to IV injection of 5-[ 18F]-ADAM). These results suggest that 5-[ 18F]-ADAM may be a potential new serotonin transporter PET imaging agent. However, due to its rapid wash-out from the brain, defluorination in vivo and lower uptake in the brain than 4-[ 18F]-ADAM, 5-[ 18F]-ADAM may not be as useful as 4-[ 18F]-ADAM as a SERT imaging agent.

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 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.