Discovery of 18F Labeled AZD5213 Derivatives as Novel Positron Emission Tomography (PET) Radioligands Targeting Histamine Subtype-3 Receptor.

Abstract

The histamine subtype 3 (H₃) receptor is an important drug target in the central nervous system (CNS), and PET imaging offers a promising technique for the noninvasive evaluation of CNS disease related to the H₃ receptor. In this study, we synthesized and evaluated the binding effects of [¹⁸F]H3-2404 and [¹⁸F]H3-2405 by modifying the structure of AZD5213, a selective H₃ antagonist. These two radioligands were prepared in high radiochemical yields and displayed stability in serum. The in vitro autoradiographic study in rat brain tissue and the following in vivo PET studies in mice demonstrated sufficient brain uptake but predominantly non-specific distribution in rodent brain. Although these data suggest that [¹⁸F]H3-2404 and [¹⁸F]H3-2405 are unsuitable as PET tracers for brain imaging of the H₃ receptor, this study provides a valuable attempt for optimizing ¹⁸F labeled radiotracers based on AZD5213.