Development of a 18F-labeled PET radioligand for imaging 5-HT1B receptors: [18F]AZ10419096.

Abstract

INTRODUCTION\nIn the last decade PET has been useful in studying and understanding the 5-HT1B receptor. [11C]AZ10419369 and [11C]P943 have been applied as radioligands in these studies. Both use carbon-11 (t1/2\u202f=\u202f20.4\u202fmin) as radionuclide, which limits the application to PET centres that have an on-site cyclotron and radiochemistry facilities. In this paper we report the synthesis and initial evaluation of the first fluorine-18 PET radioligand to image 5-HT1B receptors in brain, [18F]AZ10419096.\n\n\nMATERIALS AND METHODS\nA boronate-precursor for [18F]AZ10419096 was synthesized from an intermediate provided by AstraZeneca and was labeled with fluorine 18 using Cu-mediated radio-fluorination. [18F]AZ10419096 was used in PET baseline and pretreatment measurements in nonhuman primates. PET data were analyzed using SRTM using the cerebellum as reference region. Blood samples for radio-metabolite analysis were collected during PET measurements.\n\n\nRESULTS\nRadio-fluorination gave [18F]AZ10419096 in sufficient amounts and molar activity and with high radiochemical purity to be applied in PET measurements. In a baseline PET measurement [18F]AZ10419096 showed a high brain uptake and regional distribution consistent with reported 5-HT1B receptor densities. In a pretreatment PET measurement, AR-A000002 (2.0\u202fmg/kg) blocked the binding of [18F]AZ10419096 to 5-HT1B receptors in occipital cortex by 80%, thereby demonstrating high specific binding.\n\n\nCONCLUSION\n[18F]AZ10419096 is the first fluorine-18 PET radioligand for imaging 5-HT1B receptors in vivo with high specific binding and binding potential. [18F]AZ10419096 is a candidate for further development for use in clinical PET studies.