Synthesis and biological evaluation ofS-[11C]methylated mercaptoimidazole piperazinyl derivatives as potential radioligands for imaging 5-HT1Areceptors by positron emission tomography (PET)

Abstract

The novel 2-mercaptoimidazole derivatives, 1-[4-((2-methoxyphenyl)-1-piperazinyl)butyl]-2-mercaptoimidazole (3) and methyl[4-((2-methoxyphenyl)-1-piperazinyl))butyl] (2-mercapto-1-methylimidazol-5-yl)methanamide (8), were efficiently labelled with 11C through methylation of the thioketone function with [11C]methyl iodide. The resulting radioligands 1-[4-((2-methoxyphenyl)-1-piperazinyl))butyl]-2-thio[11C]methylimidazole ([11C]9) and methyl[4-((2-methoxyphenyl)-1-piperazinyl))butyl] (2-thio[11C]methyl-1-methylimidazol-5-yl)-methanamide ([11C]10) were synthesized in radiochemical yields of 20–30% (decay-corrected, related to [11C]CO2) at a specific radioactivity of 0.2–0.4 Ci/µmol within 40–45 min including HPLC-purification. The radiochemical purity exceeded 99%. The reference compounds 9 and 10 were tested in a competitive receptor binding assay to determine their affinity toward the 5-HT1A receptor. Both compounds exhibit excellent sub-nanomolar affinities (IC50=0.576±0.008 nM (9); IC50=0.86±0.02 nM (10)) for the 5-HT1A receptor while displaying a high selectivity towards the 5-HT2A subtype of receptors (IC50>480 nM). By contrast, compound 9 also shows substantial binding for the alpha1-adrenergic receptor (IC50=3.00±0.02 nM) when compared with compound 10 (IC50=54.5±0.6 nM). Preliminary biodistribution studies in rats showed an initial brain uptake of 1.14±0.11 and 0.37±0.04% ID/g after 5 min, which decreased to 0.18±0.04 and 0.16±0.01% ID/g after 60 min for compounds [11C]9 and [11C]10, respectively. For both compounds, the cerebellum and rest of the brain uptake are very similar at the different time points. Unlike [11C]9, the radioligand [11C]10 has significant uptake and retention in the adrenal glands. Due to their washout from the brain compounds [11C]9 and [11C]10 seem not to be good candidates as radioligands for imaging 5-HT1A receptors by PET. Copyright © 2005 John Wiley & Sons, Ltd.