Initial evaluation of 18F-GE-179, a putative PET Tracer for activated N-methyl D-aspartate receptors.

Abstract

UNLABELLED:

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.

CONCLUSION:

(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: Colm J McGinnity, Alexander Hammers, Daniela A Riaño Barros, Sajinder K Luthra, Paul A Jones, William Trigg, Caroline Micallef, Mark R Symms, David J Brooks, Matthias J Koepp, John S Duncan
• Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine (J Nucl Med) Vol. 55 Issue 3 Pg. 423-30 (Mar 2014) ISSN: 1535-5667 [Electronic] United States
• PMID: 24525206 (Publication Type: Clinical Trial, Journal Article)

Chemical References

• Guanidines
• Ligands
• Radioactive Tracers
• Receptors, N-Methyl-D-Aspartate

Topics

• Adult
• Brain (diagnostic imaging, metabolism)
• Female
• Guanidines (chemistry, metabolism)
• Humans
• Kinetics
• Ligands
• Male
• Middle Aged
• Models, Biological
• Positron-Emission Tomography (methods)
• Radioactive Tracers
• Radiochemistry
• Receptors, N-Methyl-D-Aspartate (metabolism)