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

Christine A. Parker, Nabeel Nabulsi, Daniel Holden, Shu-Fei Lin, Tara Cass, David Labaree, Steven Kealey, Antony D. Gee, Stephen M. Husbands, Darren Quelch, Richard E. Carson, David J. Nutt, Yiyun Huang, Robin J. Tyacke

Research output: Contribution to journalArticlepeer-review


The development of a PET radioligand selective for I2-imidazoline binding sites (I2BS) would enable, for the first time, specific, measurable in vivo imaging of this target protein, along with assessment of alterations in expression patterns of this protein in disease pathophysiology.

Methods: BU99008 was identified as the most promising I2BS radioligand candidate and radiolabeled with 11C via methylation. The in vivo binding properties of 11C-BU99008 were assessed in rhesus monkeys to determine brain penetration, brain distribution, binding specificity and selectivity (via the use of the unlabeled blockers), and the most appropriate kinetic model for analyzing data generated with this PET radioligand.

Results: 11C-BU99008 was demonstrated to readily enter the brain, resulting in a heterogeneous distribution (globus pallidus < cortical regions < cerebellum) consistent with the reported regional I2BS densities as determined by human tissue section autoradiography and preclinical in vivo PET studies in the pig. In vivo competition studies revealed that 11C-BU99008 displayed reversible kinetics specific for the I2BS. The multilinear analysis (MA1) model was the most appropriate analysis method for this PET radioligand in this species. The selective I2BS blocker BU224 was shown to cause a saturable, dose-dependent decrease in 11C-BU99008 binding in all regions of the brain assessed, further demonstrating the heterogeneous distribution of I2BS protein in the rhesus brain and binding specificity for this radioligand.

Conclusion: These data demonstrate that 11C-BU99008 represents a specific and selective PET radioligand for imaging and quantifying the I2BS, in vivo, in the rhesusmonkey. Further work is under way to translate the use of 11C-BU99008 to the clinic. 
Original languageEnglish
Pages (from-to)838-844
Number of pages7
JournalJournal of Nuclear Medicine
Issue number5
Publication statusPublished - 1 May 2014
Externally publishedYes


  • BU99008
  • I2BS
  • PET
  • Positron emission tomography
  • 2 (2 imidazolin 2 yl)quinoline
  • amine oxidase (flavin containing) isoenzyme A
  • amine oxidase (flavin containing) isoenzyme B
  • carbon 2 (4,5 dihydro 1h imidazol 2 yl) 1 methyl 1h indole c 11
  • carrier proteins and binding proteins
  • imidazoline 2 binding site
  • radioligand
  • unclassified drug
  • animal cell
  • animal tissue
  • article
  • binding affinity
  • binding competition
  • binding site
  • cerebellum
  • controlled study
  • drug binding
  • drug blood level
  • drug distribution
  • drug penetration
  • drug screening
  • drug synthesis
  • enzyme inhibition
  • female
  • frontal cortex
  • globus pallidus
  • human
  • human tissue
  • IC50
  • in vitro study
  • in vivo study
  • isotope labeling
  • Macaca fascicularis
  • neuroimaging
  • nonhuman
  • nuclear magnetic resonance imaging
  • MRI scanner
  • PET scanner
  • positron emission tomography
  • priority journal
  • protein analysis
  • protein expression
  • protein localization
  • radiation detection
  • radiochemistry
  • rat
  • rhesus monkey


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