Imaging imidazoline-I binding sites in porcine brain using C-BU99008

Changes in the density of imidazoline-I binding sites have been observed in a range of neurologic disorders including Alzheimer's disease, Huntington's chorea, and glial tumor; however, the precise function of these sites remains unclear. A PET probe for I binding sites would further our understanding of the target and may find application as a biomarker for early disease diagnosis. Compound BU99008 has previously been identified as a promising I ligand from autoradiography studies, displaying high affinity and good selectivity toward the target. In this study, BU99008 was radiolabeled with C in order to image the I binding sites in vivo using PET. Methods: C-BU99008 was radiolabeled by N-alkylation of the desmethyl precursor using C-methyl iodide. A series of PET experiments was performed to investigate the binding of C-BU99008 in porcine brains, in the presence or absence of a nonradiolabeled, competing I ligand, BU224. Results: C-BU99008 was obtained in good yield and specific activity. In vivo, C-BU99008 displayed good brain penetration and gave a heterogeneous distribution with high uptake in the thalamus and low uptake in the cortex and cerebellum. C-BU99008 brain kinetics were well described by the 1-tissue-compartment model, which was used to provide estimates for the total volume of distribution (V) across brain regions of interest. Baseline VT values were ranked in the following order: thalamus > striatum > hippocampus > frontal cortex ≥ cerebellum, consistent with the known distribution and concentration of I binding sites. Administration of a selective I binding site ligand, BU224, reduced the V to near-homogeneous levels in all brain regions. Conclusion: C-BU99008 appears to be a suitable PET radioligand for imaging the I binding sites in vivo.