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Evaluation of 11C-BU99008, a PET Ligand for the Imidazoline2 Binding Site in Human Brain
- Source :
- Journal of Nuclear Medicine. 59:1597-1602
- Publication Year :
- 2018
- Publisher :
- Society of Nuclear Medicine, 2018.
-
Abstract
- 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-compartment model 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.
- Subjects :
- Pathology
medicine.medical_specialty
Monoamine oxidase inhibitor
Isocarboxazid
Glial fibrillary acidic protein
biology
Chemistry
medicine.drug_class
Human brain
Pharmacology
030218 nuclear medicine & medical imaging
03 medical and health sciences
0302 clinical medicine
medicine.anatomical_structure
In vivo
medicine
biology.protein
Radioligand
Distribution (pharmacology)
Radiology, Nuclear Medicine and imaging
Idazoxan
030217 neurology & neurosurgery
medicine.drug
Subjects
Details
- ISSN :
- 2159662X and 01615505
- Volume :
- 59
- Database :
- OpenAIRE
- Journal :
- Journal of Nuclear Medicine
- Accession number :
- edsair.doi...........e9b5c2ce8425fd266c807a1f8b8560b5