Evaluation of 11 C-BU99008, a PET Ligand for the Imidazoline 2 Binding Site in Human Brain

The imidazoline binding site (I BS) 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. C-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. Fourteen healthy male volunteers underwent dynamic PET imaging with C-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 I BS/α -adrenoceptor drug idazoxan ( = 8; 20, 40, 60, and 80 mg) and the mixed irreversible monoamine oxidase type A/B inhibitor isocarboxazid ( = 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 (regional distribution volume). All image processing and kinetic analyses were performed in MIAKAT. Brain uptake of C-BU99008 was good, with reversible kinetics and a heterogeneous distribution consistent with known I BS expression. Model selection criteria indicated that the 2-tissue-compartment model was preferred. estimates were high in the striatum (105 ± 21 mL⋅cm ), medium in the cingulate cortex (62 ± 10 mL⋅cm ), and low in the cerebellum (41 ± 7 mL⋅cm ). 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% ( , ∼30 mL⋅cm ) 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. C-BU99008 in human PET studies demonstrates good brain delivery, reversible kinetics, heterogeneous distribution, specific binding signal consistent with I BS distribution, and good test-retest reliability.