title: In vivo positron emission tomography imaging with [¹¹C]ABP688: binding variability and specificity for the metabotropic glutamate receptor subtype 5 in baboons.
abstract: OBJECTIVE
  Metabotropic glutamate receptor subtype 5 (mGluR5) dysfunction has been implicated in several disorders. [(11)C]ABP688, a positron emission tomography (PET) ligand targeting mGluR5, could be a valuable tool in the development of novel therapeutics for these disorders by establishing in vivo drug occupancy. Due to safety concerns in humans, these studies may be performed in nonhuman primates. Therefore, in vivo characterization of [(11)C]ABP688 in nonhuman primates is essential.
  
  
  METHODS
  Test-retest studies were performed in baboons (Papio anubis) to compare modeling approaches and determine the optimal reference region. The mGluR5-specific antagonist 3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine (MTEP) was then used in test-block studies, in which ligand binding was measured before and after MTEP administration. Test/block data were analyzed both by calculating changes in binding and using a graphical approach, which allowed estimation of both MTEP occupancy and nonspecific binding.
  
  
  RESULTS
  Test-retest results, which have not been previously reported for [(11)C]ABP688, indicated that [(11)C]ABP688 variability is low using an unconstrained two-tissue compartment model. The most appropriate, though not ideal, reference region was found to be the gray matter of the cerebellum. Using these optimal modeling techniques on the test/block data, about 90% occupancy was estimated by the graphical approach.
  
  
  CONCLUSIONS
  These studies are the first to demonstrate the specificity of [(11)C]ABP688 for mGluR5 with in vivo PET in nonhuman primates. The results indicate that, in baboons, occupancy of mGluR5 is detectable by in vivo PET, a useful finding for proceeding to human studies, or performing further baboon studies, quantifying the in vivo occupancy of novel therapeutics targeting mGluR5.
authors.affiliation: Division of Molecular Imaging and Neuropathology, Department of Psychiatry, Columbia University College of Physicians and Surgeons, NYSPI Mail Unit 42, 1051 Riverside Drive, New York, NY, USA. cd2415@columbia.edu
authors.forename: Christine
authors.initials: C
authors.lastname: DeLorenzo
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Milak
authors.forename: Kathleen G
authors.initials: KG
authors.lastname: Brennan
authors.forename: J S Dileep
authors.initials: JS
authors.lastname: Kumar
authors.forename: J John
authors.initials: JJ
authors.lastname: Mann
authors.forename: Ramin V
authors.initials: RV
authors.lastname: Parsey
mesh_terms: D000818:Animals; D001692:Biological Transport; D002250:Carbon Radioisotopes; D008297:Male; D010091:Oximes / Q000378:metabolism*; D010215:Papio; D049268:Positron-Emission Tomography; D011485:Protein Binding; D011725:Pyridines / Q000378:metabolism*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015203:Reproducibility of Results; D013379:Substrate Specificity
chemical_list: C510950:3-(6-methylpyridin-2-ylethynyl)cyclohex-2-enone-O-methyloxime; D002250:Carbon Radioisotopes; C578935:GRM5 protein, human; D010091:Oximes; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate