title: Evaluation and initial in vitro and ex vivo characterization of the potential positron emission tomography ligand, BU99008 (2-(4,5-dihydro-1H-imidazol-2-yl)-1- methyl-1H-indole), for the imidazoline₂ binding site.
abstract: The density of the Imidazoline₂ binding site (I₂BS) has been shown to change in psychiatric conditions such as depression and addiction, along with neurodegenerative disorders such as Alzheimer's disease and Huntington's chorea. The presence of I₂BS on glial cells and the possibility that they may in some way regulate glial fibrillary acidic protein has led to increased interest into the role of I₂BS and I₂BS ligands in conditions characterized by marked gliosis. In addition, it has been suggested that I₂BS may be a marker for human glioblastomas. Therefore, the development of a positron emission tomography (PET) radioligand for the I₂BS would be of major benefit in our understanding of these conditions. We now report the successful synthesis and initial pharmacological evaluation of potential PET radioligands for the I₂BS as well as the tritiation and characterization of the most favorable of the series, BU99008 (6), both in vitro and ex vivo in rat. The series as a whole demonstrated excellent affinity and selectivity for the I₂BS, with BU99008 (6) selected as the lead candidate to be taken forward for in vivo assessment. BU99008 (6) showed very good affinity for the I₂BS (K(i) of 1.4 nM; K(d) = 1.3 nM), good selectivity compared with the α₂ -adrenoceptor (909-fold). In addition, following peripheral administration, [³H]BU99008 demonstrated a heterogenous uptake into the rat brain consistent with the known distribution of the I₂BS in vivo. This, and the amenability of BU99008 (6) to radiolabeling with a positron-emitting radioisotope, indicates its potential as a PET radioligand for imaging the I₂BS in vivo.
authors.affiliation: Neuropsychopharmacology Unit, Centre for Pharmacology and Therapeutics, Hammersmith Hospital Campus, Imperial College London, London W12 0NN, United Kingdom. r.tyacke@imperial.ac.uk
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Tyacke
authors.forename: Amy
authors.initials: A
authors.lastname: Fisher
authors.forename: Emma S J
authors.initials: ES
authors.lastname: Robinson
authors.forename: Peter
authors.initials: P
authors.lastname: Grundt
authors.forename: Emma M
authors.initials: EM
authors.lastname: Turner
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Husbands
authors.forename: Alan L
authors.initials: AL
authors.lastname: Hudson
authors.forename: Christine A
authors.initials: CA
authors.lastname: Parker
authors.forename: David J
authors.initials: DJ
authors.lastname: Nutt
mesh_terms: D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism*; D054755:Imidazoline Receptors / Q000737:chemistry* / Q000378:metabolism; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism*; D007553:Isotope Labeling; D008024:Ligands; D008297:Male; D009928:Organ Specificity; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar
chemical_list: C574081:2-(4,5-dihydro-1H-imidazol-2-yl)-1-methyl-1H-indole; D007093:Imidazoles; D054755:Imidazoline Receptors; D007211:Indoles; D008024:Ligands; C487767:imidazoline receptor 2