[11C]AZ10419096-a full antagonist PET radioligand for imaging brain 5-HT1B receptors

Introduction: The serotonergic system is widely present in all regions of the central nervous system (CNS) and plays a key modulatory role in many of its functions. Positron emission tomography (PET) is used to study several serotonin receptors in CNS in vivo. The G-protein coupled receptor 5-HT1B is mostly present in the occipital cortex and in midbrain and is linked to several psychiatric disorders. There is evidence that agonist PET radioligands for neuroreceptors are more sensitive to endogenous neurotransmitters than antagonists. Our previously developed 5-HT1B receptor PET radioligand, [C-11]AZ10419369, is now considered a partial agonist. In this work we are aiming to develop a full antagonist PET radioligand for imaging brain 5-HT1B receptors, and evaluate its sensitivity to increased endogenous serotonin concentration. 'Materials: [C-11]A210419096 was synthesized by rapid methylation of the prepared corresponding N-desmethyl precursor with [C-11]methyl triflate. Five PET measurements were performed in cynomolgus monkeys, consisting of two at baseline, one after treatment of a monkey with a 5-HT1B antagonist, AR-A000002, and two in which fenfluramine was administered during scanning to induce endogenous serotonin release. Results and discussion: [C-11]AZ10419096 was synthesized in high yield and purity within 30 min, including purification, formulation and sterile filtration. The baseline PET measurements demonstrated [C-11]AZ10419096 to have favorable radioligand characteristics, including high specific binding in brain regions that have high 5-HT1B density, such as occipital cortex and globus pallidus, as well as subsequent rapid elimination from brain and a minor abundance of lipophilic radiometabolites in plasma. AR-A00002 completely blocked radioligand receptor-specific binding. Fenfluramine produced a distinct displacement of radioligand consistent with an expected increase of synaptic endogenous serotonin concentration. Conclusions: [C-11]AZ10419096, a full 5-HT1B antagonist PET radioligand, demonstrates high specific binding in monkey brain that is sensitive to competition from a known 5-HT1B antagonist as well as to putatively increased endogenous serotonin levels. Published by Elsevier Inc.