No abstract

The development of a PET radioligand selective for I 2 -imidazoline binding sites (I 2 BS) would enable, for the first time, specific, measurable in vivo imaging of this target protein, along with assessment of alterations in expression patterns of this protein in disease pathophysiology. Methods: BU99008 was identified as the most promising I 2 BS radioligand candidate and radiolabeled with 11 C via methylation. The in vivo binding properties of 11 C-BU99008 were assessed in rhesus monkeys to determine brain penetration, brain distribution, binding specificity and selectivity (via the use of the unlabeled blockers), and the most appropriate kinetic model for analyzing data generated with this PET radioligand. Results: 11 C-BU99008 was demonstrated to readily enter the brain, resulting in a heterogeneous distribution (globus pallidus . cortical regions . cerebellum) consistent with the reported regional I 2 BS densities as determined by human tissue section autoradiography and preclinical in vivo PET studies in the pig. In vivo competition studies revealed that 11 C-BU99008 displayed reversible kinetics specific for the I 2 BS. The multilinear analysis (MA1) model was the most appropriate analysis method for this PET radioligand in this species. The selective I 2 BS blocker BU224 was shown to cause a saturable, dose-dependent decrease in 11 C-BU99008 binding in all regions of the brain assessed, further demonstrating the heterogeneous distribution of I 2 BS protein in the rhesus brain and binding specificity for this radioligand. Conclusion: These data demonstrate that 11 C-BU99008 represents a specific and selective PET radioligand for imaging and quantifying the I 2 BS, in vivo, in the rhesus monkey. Further work is under way to translate the use of 11 C-BU99008 to the clinic.