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 imidazoline ₂ binding site

The density of the Imidazoline ₂ binding site (I ₂BS) 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 I ₂BS 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 I ₂BS and I ₂BS ligands in conditions characterized by marked gliosis. In addition, it has been suggested that I ₂BS may be a marker for human glioblastomas. Therefore, the development of a positron emission tomography (PET) radioligand for the I ₂BS 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 I ₂BS 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 I ₂BS, with BU99008 (6) selected as the lead candidate to be taken forward for in vivo assessment. BU99008 (6) showed very good affinity for the I ₂BS (K _i of 1.4 nM; K _d = 1.3 nM), good selectivity compared with the α ₂-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 I ₂BS 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 I ₂BS in vivo.