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-HT1AReceptor Agonist Positron Emission Tomography Ligand

Antagonist 5-HT1A 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 (Ki = 1.36 nM) 5-HT1A agonist PET tracer is described. Piperazine 10 is a 5-HT1A 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-HT1A receptors. Binding of [11C]10 was blocked by WAY100635 and 8-OH-DPAT. The regional brain volumes of distribution (VT) of [11C]10 in baboon correlate with [11C]WAY100635 VT in baboons. These data provide evidence that [11C]10 is the first promising agonist PET tracer for the 5-HT1A receptors.