RT Journal Article
SR Electronic
T1 Evaluation of 11C-BU99008, a PET Ligand for the Imidazoline2 Binding Sites in Rhesus Brain
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 838
OP 844
DO 10.2967/jnumed.113.131854
VO 55
IS 5
A1 Christine A. Parker
A1 Nabeel Nabulsi
A1 Daniel Holden
A1 Shu-fei Lin
A1 Tara Cass
A1 David Labaree
A1 Steven Kealey
A1 Antony D. Gee
A1 Stephen M. Husbands
A1 Darren Quelch
A1 Richard E. Carson
A1 David J. Nutt
A1 Yiyun Huang
A1 Robin J. Tyacke
YR 2014
UL http://jnm.snmjournals.org/content/55/5/838.abstract
AB 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 rhesus monkey. Further work is under way to translate the use of 11C-BU99008 to the clinic.