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-HT1A receptor agonist positron emission tomography ligand.

Antagonist 5-HT 1 A PET ligands are available, but an agonist ligand would give more information about signal transduction capacity. Synthesis and in vivo evaluation of [0-methyl- 1 1 C]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 1 A agonist PET tracer is described. Piperazine 10 is a 5-HT 1 A agonist with an EC 5 0 comparable to serotonin, based on cAMP formation and GTPyS binding assays. Radiosynthesis of [ 1 1 C]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 [ 1 1 C]CH 3 OTf in 25 ′ 5% (n = 15) yield at the end of synthesis (EOS). The chemical and radiochemical purities of [ 1 1 C]10 were >99% with a specific activity 1500 ′ 300 Ci/mmol (n =15). PET studies in anesthetized baboon demonstrate [ 1 1 C]10 specific binding in brain regions rich in 5-HT 1 A receptors. Binding of [ 1 1 C]10 was blocked by WAY100635 and 8-OH-DPAT. The regional brain volumes of distribution (V T ) of [ 1 1C]10 in baboon correlate with [ 1 1 C]WAY100635 V T in baboons. These data provide evidence that ["C]10 is the first promising agonist PET tracer for the 5-HT 1 A receptors.