Synthesis and biological evaluation of S-[¹¹C]methylated mercaptoimidazolde piperazinyl derivatives as potential radioligands for imaging 5-HT_1A receptors by positron emission tomography (PET)

The novel 2-mercaptoimidazolde derivatives, 1-[4-((2-methoxyphenyl)-1-piperazinyl)-butyl]-2-mercaptoimidazolde (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-HT_1A recptor. Both compounds exhibit excellent sub-nanomolar affinities (IC₅₀ = 0.576 ± 0.008 nM (9); IC₅₀ = 0.86 ± 0.02 nM (10)) for the 5-HT_1A receptor while displaying a high selectivity towards the 5-HT_2A subtype of receptors (IC₅₀ > 480 nM). By contrast, compound 9 also shows substantial binding for the alpha-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 condidates as radioligands for imaging 5-HT_1A receptors by PET.