title: Initial evaluation of 18F-GE-179, a putative PET Tracer for activated N-methyl D-aspartate receptors.
abstract: N-methyl D-aspartate (NMDA) ion channels play a key role in a wide range of physiologic (e.g., memory and learning tasks) and pathologic processes (e.g., excitotoxicity). To date, suitable PET markers of NMDA ion channel activity have not been available. (18)F-GE-179 is a novel radioligand that selectively binds to the open/active state of the NMDA receptor ion channel, displacing the binding of (3)H-tenocyclidine from the intrachannel binding site with an affinity of 2.4 nM. No significant binding was observed with 10 nM GE-179 at 60 other neuroreceptors, channels, or transporters. We describe the kinetic behavior of the radioligand in vivo in humans.
  
  
  METHODS
  Nine healthy participants (6 men, 3 women; median age, 37 y) each underwent a 90-min PET scan after an intravenous injection of (18)F-GE-179. Continuous arterial blood sampling over the first 15 min was followed by discrete blood sampling over the duration of the scan. Brain radioactivity (KBq/mL) was measured in summation images created from the attenuation- and motion-corrected dynamic images. Metabolite-corrected parent plasma input functions were generated. We assessed the abilities of 1-, 2-, and 3-compartment models to kinetically describe cerebral time-activity curves using 6 bilateral regions of interest. Parametric volume-of-distribution (V(T)) images were generated by voxelwise rank-shaping regularization of exponential spectral analysis (RS-ESA).
  
  
  RESULTS
  A 2-brain-compartment, 4-rate-constant model best described the radioligand's kinetics in normal gray matter of subjects at rest. At 30 min after injection, 37% of plasma radioactivity represented unmetabolized (18)F-GE-179. The highest mean levels of gray matter radioactivity were seen in the putamina and peaked at 7.5 min. A significant positive correlation was observed between K1 and V(T) (Spearman ρ = 0.398; P = 0.003). Between-subject coefficients of variation of V(T) ranged between 12% and 16%. Voxelwise RS-ESA yielded similar V(T)s and coefficients of variation.
  
  
  CONCLUSIONS
  (18)F-GE-179 exhibits high and rapid brain extraction, with a relatively homogeneous distribution in gray matter and acceptable between-subject variability. Despite its rapid peripheral metabolism, quantification of (18)F-GE-179 VT is feasible both within regions of interest and at the voxel level. The specificity of (18)F-GE-179 binding, however, requires further characterization with in vivo studies using activation and disease models.
authors: Division of Brain Sciences, Department of Medicine, Imperial College London, London, United Kingdom.
authors: Colm J
authors: CJ
authors: McGinnity
authors: Alexander
authors: A
authors: Hammers
authors: Daniela A
authors: DA
authors: Riaño Barros
authors: Sajinder K
authors: SK
authors: Luthra
authors: Paul A
authors: PA
authors: Jones
authors: William
authors: W
authors: Trigg
authors: Caroline
authors: C
authors: Micallef
authors: Mark R
authors: MR
authors: Symms
authors: David J
authors: DJ
authors: Brooks
authors: Matthias J
authors: MJ
authors: Koepp
authors: John S
authors: JS
authors: Duncan
mesh_terms: D000328:Adult; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D006146:Guanidines / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D049268:Positron-Emission Tomography / Q000379:methods*; D011849:Radioactive Tracers; D011854:Radiochemistry; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D006146:Guanidines; D008024:Ligands; D011849:Radioactive Tracers; D016194:Receptors, N-Methyl-D-Aspartate
keywords: CNS 5161; GE-179; NMDA; PET