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 degrees C followed by reduction with NaBH(4)- Cu(OAc)(2) in EtOH at 78 degrees C and purification with HPLC gave compound 12a in approximately 5-10% yield in a synthesis time of 150min from EOB. A preliminary biodistribution study in rats showed that the uptake of compound 12a in rat brain was high (approximately 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 1h post-injection. These results suggest that compound 12a may be a potential new serotonin transporter PET imaging agent.
Shiue
Grace G
GG
Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Fang
Ping
P
Shiue
Chyng-Yann
CY
D000818:Animals; D001592:Benzyl Alcohols; D001596:Benzylamines / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000032:analysis*; D002531:Cerebellum / Q000378:metabolism; D018360:Crystallography, X-Ray; D005462:Fluorine Radioisotopes; D007031:Hypothalamus / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000032:analysis*; D026901:Membrane Transport Proteins; D015394:Molecular Structure; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins; D014055:Tomography, Emission-Computed / Q000379:methods
C098110:403U76; D001592:Benzyl Alcohols; D001596:Benzylamines; D002352:Carrier Proteins; D005462:Fluorine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; C475911:N,N-dimethyl-2-(2-amino-4-fluorophenylthio)benzylamine; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat