Synthesis and in Vivo Validation of [O-Methyl-~(11)C]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

摘要

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-~(11)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_(1A) agonist PET tracer is described.Piperazine 10 is a 5-HT_(1A) agonist with an EC_(50) comparable to serotonin,based on cAMP formation and GTP_(gamma)S binding assays.Radiosynthesis of [~(11)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 [~(11)C]CH_3OTf in 25+-5% (n=15) yield at the end of synthesis (EOS).The chemical and radiochemical purities of [~(11)C]10 were >99% with a specific activity 1500+-300 Ci/mmol (n =15).PET studies in anesthetized baboon demonstrate [~(11)C]10 specific binding in brain regions rich in 5-HT_(1A) receptors.Binding of [~(11)C]10 was blocked by WAY100635 and 8-OH-DPAT.The regional brain volumes of distribution (V_T) of [~(11)C]10 in baboon correlate with [~(11)C]WAY100635 V_T in baboons.These data provide evidence that [~(11)C]10 is the first promising agonist PET tracer for the 5-HT_(1A) receptors.