C-Labeled 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1-3-benzazepin-7-yl)oxy]--methyl-3-pyridinecarboxamide hydrochloride

Histamine mediates its activity in the central nervous system (CNS) and the peripheral tissue through four G protein–coupled receptor subtypes (HRs) designated as H, H, H, and H (1). Among these receptors, the H subtype that is found primarily in the CNS appears to control several normal physiological processes and is believed to be involved in the development of schizophrenia, epilepsy, attention deficit hyperactive disorder, and Alzheimer’s disease (2). In addition, the H receptor (HR) is also known to regulate the synthesis and release of histamine itself and other neurotransmitters such as noradrenalin, dopamine, and acetylcholine (1, 2). Several clinical trials approved by the United States Food and Drug Administration (FDA) have either been completed or are in progress to evaluate drugs that modulate HRs for the treatment of diseases involving these receptors. Evidence suggesting the involvement of the HR in a variety of physiological and pathological processes has been obtained only from postmortem studies performed on the human brain, and to confirm these observations investigators believe that it is necessary to perform studies using non-invasive techniques under conditions. Several imaging agents have been developed and evaluated for use with non-invasive techniques such as positron emission tomography (PET) and single-photon emission computed tomography to investigate the HR in the brain, but these probes either have a limited uptake in the tissue or show low specificity for or binding to the receptor (2). Recently, two radiolabeled inverse-agonist (3) PET agents with suitable characteristics for the quantification and imaging of the HR have been reported, but these compounds are still under evaluation (4). In a continued effort to develop HR antagonist or reverse-agonist compounds, Medhurst et al. synthesized 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1-3-benzazepin-7-yl)oxy]--methyl-3-pyridinecarboxamide hydrochloride (GSK189254) and showed that it had a high selectivity for HR under conditions (5). In addition, the compound was reported to improve the memory and cognitive function of rats with impaired memory and cognition activity, indicating that the drug could be suitable for treating cognitive disorders or dementia in Alzheimer’s disease patients. A GSK189254-duloxetine combination has also been evaluated in a clinical trial for the treatment of electrical hyperalgesia in healthy volunteers; however, no results are as yet available for this study. Because of its activity and structural characteristics, Plisson et al. labeled GSK189254 with C ([C]-GSK189254) and evaluated [C]-GSK189254 as a PET imaging agent for HR under and conditions in porcine (pig) brain (2). The biodistribution of [C]-GSK189254 in the brain of individuals with mild cognitive impairment has been studied, but, although no publication reporting the results is currently available, the labeled compound appears to be suitable for the quantification of HR in humans, as suggested by Hamill et al. (4).