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

The histamine H-3 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 F-18-labeled high-affinity H3R antagonist F-18-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/mu mol. F-18-ST889 exhibited high in vivo stability and rather low lipophilicity (logD(7.4) = 0.35 +/- 0.09). In vitro autoradiography showed specific binding in H3R-rich brain regions such as striatum and cortex. However, in vivo PET imaging of the rat brain with F-18-ST889 was not successful. Possible reasons are discussed. (C) 2012 Elsevier Ltd. All rights reserved.