Radiofluorinated histamine H3 receptor antagonist as a potential probe for in vivo PET imaging: Radiosynthesis and pharmacological evaluation

Article abstract of DOI:10.1016/j.bmc.2012.03.024

The histamine H₃ receptor (H₃R) plays a role in cognition and memory processes and is implicated in different neurological disorders, including Alzheimer's disease, schizophrenia, and narcolepsy. In vivo studies of the H₃R occupancy using a radiolabeled PET tracer would be very useful for CNS drug discovery and development. We report here the radiosynthesis, in vitro and in vivo evaluation of a novel ¹⁸F- labeled high-affinity H₃R antagonist ¹⁸F-ST889. The radiosynthesis was accomplished via nucleophilic substitution of the mesylate leaving group with a radiochemical yield of 8-20%, radiochemical purity >99%, and specific radioactivity >65 GBq/μmol. ¹⁸F-ST889 exhibited high in vivo stability and rather low lipophilicity (log D_7.4 = 0.35 ± 0.09). In vitro autoradiography showed specific binding in H ₃R-rich brain regions such as striatum and cortex. However, in vivo PET imaging of the rat brain with ¹⁸F-ST889 was not successful. Possible reasons are discussed.