SYNTHESIS AND BIOLOGICAL INVESTIGATIONS OF [F-18] MR18445, A 5-HT3 RECEPTOR PARTIAL AGONIST

F-18 Labelled MR18445 uorobenzyl)piperazino]-7-methoxypyrrolo[1,2-alph a] quinoxaline), a selective 5-HT3 receptor partial agonist with nanom olar affinity, was synthesized and examined as a potential radioligand for PET imaging of brain 5HT(3) receptors. Radiotracer was prepared b y N-alkylation of the MR18491 precursor with 4-[F-18]fluorobenzyl iodi de. This latter was synthesized in a three-step procedure from 4-[F-18 ]fluorobenzaldehyde obtained by F-18-nucleophilic displacement of 4-ni trobenzaldehyde, subsequently reduced to 4-[F-18]fluorobenzyl alcohol and converted into reactive 4-[F-18]fluorobenzyl iodide. The reduction step was performed on a column filled with NaBH4/Al2O3 and 4-[F-18]fl uorobenzyl alcohol was obtained with high reproducible yield (82-93% f rom 4-[F-18]fluorobenzaldehyde) if there were traces of water in the s ystem. The radiosynthesis of [F-18]MR18445 required approximately 120 min. Semi-preparative HPLC purification followed by formulation gave i njectable solutions of [F-18]MR18445 with a radiochemical purity > 99% . The overall yield of the synthesis was mainly dependent upon the fir st step efficiency of aromatic incorporation of F-18- and varied from 12% to 29%. All the synthetic procedure was realized on a ZYMARK robot ic system. Biological in vivo studies in rats showed that uptake of [F -18]MR18445 in brain was rapid and high. No evidence of radiolabeled m etabolites could be observed in the brain as late as 40 min after inje ction, despite the rapid appearance of metabolites in the plasma. Howe ver, neither phosphorimaging autoradiographic studies in rats nor PET experiments in baboons revealed specific binding of the radiotracer in brain, suggesting [F-18]MR18445 is not suitable for 5-HT3 receptors P ET studies. (C) 1998 Elsevier Science Ltd. All rights reserved.