in vivo Variation in Metabotropic Glutamate Receptor Subtype 5 Binding Using Positron Emission Tomography and [¹¹C]ABP688

Abstract

The metabotropic glutamate receptor subtype 5 (mGluR5) has been implicated in the pathophysiology of mood and anxiety disorders. Recently, a positron emission tomography (PET) tracer exhibiting high selectivity and specificity for mGluR5, 3-(6-methyl-pyridin-2-ylethynyl)-cyclohex-2-enone-O-11 C-methyl-oxime ([ 11 C]ABP688), was developed. In this work, eight healthy adult male humans were imaged twice to assess within-subject [ 11 C]ABP688 binding variability using PET. In seven of the eight subjects, significantly higher binding was observed during the second (retest) scan. This binding increase could not be definitively explained by differences in ligand injected mass or dose, or changes in metabolism between scans. In addition, this type of systematic binding increase was not observed in a [ 11 C]ABP688 test-retest study performed by our group on anaesthetized baboons. It is therefore possible that the increased binding was because of physiological changes occurring between scans, such as changes in endogenous glutamate levels. If PET imaging with [ 11 C]ABP688 could detect such differences, as preliminary evidence suggests, it could be used to help uncover the role of glutamate in the pathophysiology of brain disorders. However, regardless of its ability to detect endogenous glutamate differences, [ 11 C]ABP688 binding variability could make accurate assessments of drug occupancy or group differences using this ligand difficult.

Kinetic Analysis of the Metabotropic Glutamate Subtype 5 Tracer [18F]FPEB in Bolus and Bolus-Plus-Constant-Infusion Studies in Humans

“…11 However, a [ 11 C]ABP688 test-retest study in humans showed a significant increase in binding parameters in the second scan, which is currently unexplained. 12 [ 18 F]SP203 also displayed regional uptake consistent with the known distribution of mGluR5. Its TACs were well fitted by the 2TC model, 13 and V T values calculated by the equilibrium method were correlated with those from the 2TC model.…”

N-Acetylcysteine– and MK-801–Induced Changes in Glutamate Levels Do Not Affect In Vivo Binding of Metabotropic Glutamate 5 Receptor Radioligand 11C-ABP688 in Rat Brain

“…Further, the small-animal PET test-retest data indicated that the 11 C-ABP688 tracer bound specifically and stably in delineated structures of the rat brain, such as the caudate putamen, cerebral cortex, frontal cortex, hippocampus, and thalamus, with BP ND s correlating closely with those in the literature (8,9). A human 11 C-ABP688 test-retest study recently revealed higher binding in the retest condition than in the test condition, and this finding could not be attributed to injected mass, dose, or clearance (24). The origin of this finding remains to be elucidated because, in our own rat study as well as in previous rat (9), baboon (4,25), and rhesus monkey (26) studies, stable testretest results with low within-subject variability were observed.…”

18F-FPEB, a PET Radiopharmaceutical for Quantifying Metabotropic Glutamate 5 Receptors: A First-in-Human Study of Radiochemical Safety, Biokinetics, and Radiation Dosimetry

“…The high test-retest variability in humans with 11 C-ABP688 may make it a less than ideal ligand for receptor quantification (41). A possible disadvantage of FPEB may be the low radiochemical yield, although the amounts of tracer that can be synthesized are sufficient for human studies and, at Johns Hopkins University, are more than adequate for routine human PET studies.…”