Evaluation of ¹¹C-BU99008, a PET Ligand for the Imidazoline₂ Binding Site in Human Brain

Abstract

The imidazoline binding site (IBS) 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 IBS/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 IBS 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 IBS distribution, and good test-retest reliability.

Longitudinal association between astrocyte function and glucose metabolism in autosomal dominant Alzheimer’s disease

“…Another promising astrocyte PET biomarker in development is 11 C-BU99008 [39]. This tracer labels imidazoline receptors predominantly found in astrocytes.…”

“…Presently there are several PET tracers available for imaging microglia, with varying degrees of success, but 11 C-DED is the only tracer to date considered to measure astrocyte function that has published longitudinal data available [ 16 ]. Another promising astrocyte PET biomarker in development is 11 C-BU99008 [ 39 ]. This tracer labels imidazoline receptors predominantly found in astrocytes.…”

Chronic inflammation in multiple sclerosis — seeing what was always there

“…Other PET radioligands target proteins that are believed to be relatively selectively expressed in astrocytes, although these radioligands have yet to be applied to the study of MS. 11 C-DED binds to mitochondrial monoamine oxidase B, which is expressed predominantly in astrocytes. The PET signal with this ligand is increased in regions of dense astrocytosis in Creuzfeldt-Jakob disease 138 and in Alzheimer disease 139 , suggesting potential for its use in MS. An alternative PET radioligand characterized in humans is 11 C-BU99008, which targets the imidazoline-2 binding site that is thought to be found predominantly in astrocytes and is implicated in regulating expression of glial fibrillary acidic protein 140 . The usefulness of this radioligand for MS has not yet been explored, although one potential disadvantage now is that the specific target protein (or proteins) has not been identified.…”

Prospects and challenges of imaging neuroinflammation beyond TSPO in Alzheimer’s disease

“…The novel PET tracer 11 C-BU99008 has been characterised in preclinical species and demonstrated to be suitable to quantify cerebral I 2 BS density, as determined in rat [115], pig [116], and rhesus monkey [117]. More recently, 11 C-BU99008 was found to have good kinetic properties in healthy human brain, with low affinity to MAO-A/MAO-B [118]. Studies in MCI and AD patients are underway to compare the regional distribution of 11 C-BU99008 with that of Aβ and 18 F-FDG-PET retention [119].…”