| 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. |
