Synthesis , biological and autoradiographic evaluation of a novel Tc-99m radioligand derived from WAY 100635 with high-affinity for the 5-HT_1A receptor and the alpha1-adrenergic receptor

This paper reports synthesis, biological evaluation, in vitro and ex vivo autoradiography of the first Tc-99m ligand with subnanomolar affinity for the 5-HT_1A receptor and a remarkably high affinity for the alpha1-adrenergicreceptor. The neutral "3+1" mixed-ligand complex combines 4-(6-mercaptohexyl)-1-(2-methoxyphenyl)piperazine as monodentate and 3-(N-methyl)azapentane-1,5-dithiol as tridentate unit with oxotechnetium(V). The analogous rhenium complex was synthesized for complete structural characterization and used in receptor binding assays. In competition experiments both complexes display subnanomolar affinity for the 5-HT_1A receptor (IC₅₀ 0.24 nM for Re, 0.13 nM for Tc) but also very high affinities for the alpha1-adrenergic receptor (IC₅₀ 0.05 nM for Re, 0.03 nM for Tc). Biodistribution studies show a brain uptake in rat of 0.22 % ID five minutes post injection. In vitro autoradiographic studies in rat brain and postmortem human brain indicate the accumulation of the Tc-99m complex in brain areas which are rich in 5-HT_1A receptors or in alpha1-adrenergic receptors. This in vitro enrichment can be blocked respectively by the 5-HT_1A receptor agonist 8-OH-DPAT or by prazosin hydrochloride, an alpha1-adrenergic receptor antagonist. Ex vivo autoradiographic studies in rats show a slight accumulation of the Tc-99m complex in 5-HT_1A receptor-rich areas of the brain which could not be blocked, as well as in regions rich in alpha1-adrenergic receptors, which could be blocked by prazosin hydrochloride.