Evaluation of ¹¹C-BU99008, a PET Ligand for the Imidazoline₂ binding site in human brain

The imidazoline₂ binding site (I₂BS) is thought to be expressed in glia and implicated in the regulation of glial fibrillary acidic protein. A PET ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. ¹¹C-BU99008 has previously been identified as a putative PET radioligand. Here, we present the first in vivo characterization of this PET radioligand in humans and assess its test-retest reproducibility. Methods: Fourteen healthy male volunteers underwent dynamic PET imaging with ¹¹C-BU99008 and arterial sampling. Six subjects were used in a test-retest assessment, and 8 were used in a pharmacologic evaluation, undergoing a second or third heterologous competition scan with the mixed I₂BS/α₂-adrenoceptor drug idazoxan (n = 8; 20, 40, 60, and 80 mg) and the mixed irreversible monoamine oxidase type A/B inhibitor isocarboxazid (n = 4; 50 mg). Regional time-activity data were generated from arterial plasma input functions corrected for metabolites using the most appropriate model to derive the outcome measure V_T (regional distribution volume). All image processing and kinetic analyses were performed in MIAKAT. Results: Brain uptake of ¹¹C-BU99008 was good, with reversible kinetics and a heterogeneous distribution consistent with known I₂BS expression. Model selection criteria indicated that the 2-tissue-compartmentmodel was preferred. V_T estimates were high in the striatum (105 ± 21 mL.cm^-3), medium in the cingulate cortex (62 ± 10 mL.cm^-3), and low in the cerebellum (41 ± 7 mL.cm^-3). Test-retest reliability was reasonable. The uptake was dose-dependently reduced throughout the brain by pretreatment with idazoxan, with an average block across all regions of about 60% (V_T, -30 mL.cm^-3) at the highest dose (80 mg). The median effective dose for idazoxan was 28 mg. Uptake was not blocked by pretreatment with the monoamine oxidase inhibitor isocarboxazid. Conclusion: ¹¹C-BU99008 in human PET studies demonstrates good brain delivery, reversible kinetics, heterogeneous distribution, specific binding signal consistent with I₂BS distribution, and good test-retest reliability.