Synthesis and biological evaluation of S-[11C]methylated mercaptoimidazole piperazinyl derivatives as potential radioligands for imaging 5-HT1A receptors by positron emission tomography (PET)

✍ Scribed by Raquel Garcia; Catarina Xavier; António Paulo; Isabel Santos; Torsten Kniess; R. Bergmann; Frank Wüst

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: French
• Weight: 157 KB
• Volume: 48
• Category: Article
• ISSN: 0022-2135
• DOI: 10.1002/jlcr.924

✦ Synopsis

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 11 C through methylation of the thioketone function with [ 11 C]methyl iodide. The resulting radioligands 1-[4-((2-methoxyphenyl)-1-piperazinyl))butyl]-2-thio[ 11 C]methylimidazole ([ 11 C]9) and methyl[4-((2-methoxyphenyl)-1-piperazinyl))butyl] (2thio[ 11 C]methyl-1-methylimidazol-5-yl)-methanamide ([ 11 C]10) were synthesized in radiochemical yields of 20-30% (decay-corrected, related to [ 11 C]CO 2 ) at a specific radioactivity of 0.2-0.4 Ci/mmol 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-HT 1A receptor.

Both compounds exhibit excellent sub-nanomolar affinities (IC 50 =0.576 AE 0.008 nM (9); IC 50 =0.86 AE 0.02 nM (10)) for the 5-HT 1A receptor while displaying a high selectivity towards the 5-HT 2A subtype of receptors (IC 50 >480 nM). By contrast, compound 9 also shows substantial binding for the alpha1-adrenergic receptor (IC 50 =3.00 AE 0.02 nM) when compared with compound 10 (IC 50 =54.5 AE 0.6 nM). Preliminary biodistribution studies in rats showed an initial