Synthesis and in vivo validation of [O-methyl-¹¹C]2-{4-[4-(7- methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3, 5-dione: A novel 5-HT_1A receptor agonist positron emission tomography ligand

Antagonist 5-HT_1A PET ligands are available, but an agonist ligand would give more information about signal transduction capacity. Synthesis and in vivo evaluation of [O-methyl-¹¹C]2-{4-[4-(7- methoxynaphthalen-1-yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3, 5-dione (10), a potential high affinity (K_i = 1,36 nM) 5-HT _1A agonist PET tracer is described. Piperazine 10 is a 5-HT _1A agonist with an EC₅₀ comparable to serotonin, based on cAMP formation and GTPγS binding assays. Radiosynthesis of [ ¹¹C]10 has been achieved by reacting 2-{4-[4-(7-hydroxynaphthalen-1- yl)piperazin-1-yl]butyl}-4-methyl-2H-[1,2,4]triazine-3,5-dione (9) and [ ¹¹C]CH₃OTf in 25 ± 5% (n = 15) yield at the end of synthesis (EOS). The chemical and radiochemical purities of [¹¹C]10 were >99% with a specific activity 1500 ± 300 Ci/mmol (n = 15). PET studies in anesthetized baboon demonstrate [¹¹C]10 specific binding in brain regions rich in 5-HT_1A receptors. Binding of [ ¹¹C]10 was blocked by WAY100635 and 8-OH-DPAT. The regional brain volumes of distribution (V_T) of [¹¹C]10 in baboon correlate with [¹¹C]WAY100635 V_T in baboons. These data provide evidence that [¹¹C]10 is the first promising agonist PET tracer for the 5-HT_1A receptors.