Imaging Imidazoline-I2Binding Sites in Porcine Brain Using11C-BU99008

UNLABELLED: Changes in the density of imidazoline-I(2) 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(2) 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(2) ligand from autoradiography studies, displaying high affinity and good selectivity toward the target. In this study, BU99008 was radiolabeled with (11)C in order to image the I(2) binding sites in vivo using PET. METHODS: (11)C-BU99008 was radiolabeled by N-alkylation of the desmethyl precursor using (11)C-methyl iodide. A series of PET experiments was performed to investigate the binding of (11)C-BU99008 in porcine brains, in the presence or absence of a nonradiolabeled, competing I(2) ligand, BU224. RESULTS: (11)C-BU99008 was obtained in good yield and specific activity. In vivo, (11)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. (11)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(T)) across brain regions of interest. Baseline V(T) values were ranked in the following order: thalamus > striatum > hippocampus > frontal cortex ≥ cerebellum, consistent with the known distribution and concentration of I(2) binding sites. Administration of a selective I(2) binding site ligand, BU224, reduced the V(T) to near-homogeneous levels in all brain regions. CONCLUSION: (11)C-BU99008 appears to be a suitable PET radioligand for imaging the I(2) binding sites in vivo.