Evaluation and initial in vitro and ex vivo characterization of the potential positron emission tomography ligand, BU99008 (2‐(4,5‐Dihydro‐1 H ‐imidazol‐2‐yl)‐1‐ methyl‐1 H ‐indole), for the imidazoline 2 binding site

The density of the Imidazoline 2 binding site (I 2 BS) 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 2 BS 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 2 BS and I 2 BS ligands in conditions characterized by marked gliosis. In addition, it has been suggested that I 2 BS may be a marker for human glioblastomas. Therefore, the development of a positron emission tomography (PET) radioligand for the I 2 BS 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 2 BS 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 2 BS, 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 2 BS ( 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, [ 3 H]BU99008 demonstrated a heterogenous uptake into the rat brain consistent with the known distribution of the I 2 BS 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 2 BS in vivo. Synapse, 2012. © 2012 Wiley Periodicals, Inc.