A useful PET probe [¹¹C]BU99008 with ultra-high specific radioactivity for small animal PET imaging of I₂-imidazoline receptors in the hypothalamus

Introduction: A positron emission tomography (PET) probe with ultra-high specific radioactivity (SA) enables measuring high receptor specific binding in brain regions by avoiding mass effect of the PET probe itself. It has been reported that PET probe with ultra-high SA can detect small change caused by endogenous or exogenous ligand. Recently, Kealey et al. developed [¹¹C]BU99008, a more potent PET probe for I₂-imidazoline receptors (I₂Rs) imaging, with a conventional SA (mean 76 GBq/μmol) showed higher specific binding in the brain. Here, to detect small change of specific binding for I₂Rs caused by endogenous or exogenous ligand in an extremely small region, such as hypothalamus in the brain, we synthesized and evaluated [¹¹C]BU99008 with ultra-high SA as a useful PET probe for small-animal PET imaging of I₂Rs. Methods: [¹¹C]BU99008 was prepared by [¹¹C]methylation of N-desmethyl precursor with [¹¹C]methyl iodide. Biodistribution, metabolite analysis, and brain PET studies were conducted in rats. Results: [¹¹C]BU99008 with ultra-high SA in the range of 5400–16,600 GBq/μmol were successfully synthesized (n = 7), and had appropriate radioactivity for in vivo study. In the biodistribution study, the mean radioactivity levels in all investigated tissues except for the kidney did not show significant difference between [¹¹C]BU99008 with ultra-high SA and that with conventional SA. In the metabolite analysis, the percentage of unchanged [¹¹C]BU99008 at 30 min after the injection of probes with ultra-high and conventional SA was similar in rat brain and plasma. In the PET study of rats' brain, radioactivity level (AUC_{30–60 min}) in the hypothalamus of rats injected with [¹¹C]BU99008 with ultra-high SA (64 [SUV ∙ min]) was significantly higher than that observed for that with conventional SA (50 [SUV ∙ min]). The specific binding of [¹¹C]BU99008 with ultra-high SA (86% of total binding) for I₂R was higher than that of conventional SA (76% of total binding). Conclusion: A PET study using [¹¹C]BU99008 with ultra-high SA would thus contribute to the detection of small changes in or small regions with I₂R expression and hence may be useful in elucidating new functions of I₂R.