Evaluation of11C-BU99008, a positron emission tomography ligand for the Imidazoline2binding site in human brain
Journal of Nuclear Medicine
The imidazoline 2 binding sites (I 2 BS), are thought to be expressed in glia, and implicated in the regulation of glial fibrillary acidic protein. A positron emission tomography (PET) ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. 11 C-BU99008 has previously been identified as a putative PET radioligand. Here we present the first in vivo characterisation of this PET radioligand in humans and assess its test-retest
... t-retest reproducibility. Methods: 14 healthy male volunteers underwent dynamic PET imaging with 11 C-BU99008 and arterial sampling. Six subjects were used to assess test-retest and eight were used in the pharmacological evaluation, undergoing a second, or third heterologous competition scan with the mixed I 2 BS/α 2 -adrenoceptor drug, idazoxan (n=8; 20, 40, 60 and 80 mg) and the mixed irreversible monoamine oxidase (MAO) A/B inhibitor, isocarboxazid (n=4; 50 mg), respectively. 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 total distribution volume). All image processing and kinetic analysis was performed in MIAKAT™ (www.miakat.org). Results: Brain uptake of 11 C-BU99008 was good with reversible kinetics and a heterogeneous distribution consistent with known I 2 BS expression. Model selection criteria indicated that the 2-tissue-compartment was preferred. V T estimates were high in the striatum (105±21 mLcm -3 ), medium in cingulate cortex (62±10 mLcm -3 ) and low in the cerebellum (41±7 mLcm -3 ). Test-retest reliability was found to be reasonable. The uptake was dose-dependently reduced by pre-treatment with idazoxan throughout the brain, with an average block across all regions of ~60% (V T ≅30 mLcm -3 ) at the highest dose (80 mg). The median effective dose (ED 50 ) for idazoxan was calculated as 28 mg. Uptake was not blocked by pre-treatment with the MAO inhibitor, isocarboxazid. Conclusions: In summary, 11 C-BU99008 in human PET studies demonstrates good brain delivery, reversible kinetics, heterogeneous distribution specific binding signal consistent with I 2 BS distribution and good test-retest reliability.