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

Abstract

Abnormal glutamate transmission is involved in various neurologic disorders, such as epilepsy, schizophrenia, and Parkinson disease. At present, no imaging techniques are capable of measuring acute fluctuations in endogenous glutamate levels in vivo. We evaluated the potential of 11 C-ABP688, a PET ligand that binds to an allosteric site of the metabotropic glutamate 5 receptor, in rats by using small-animal PET and b-microprobes after pharmacologic challenges with N-acetylcysteine (NAc) and MK-801. Both compounds are known to induce increases in endogenous glutamate levels. Methods: Three experiments with 11 C-ABP688 were performed to validate our study setup: first, metabolite analyses during workup (n 5 3) and after a selected treatment (n 5 3); second, a test-retest (n 5 12) small-animal PET experiment (1 h scan; 27.75 MBq of 11 C-ABP688 administered intravenously; ,3 nmol/kg); and third, a small-animal PET and b-microprobe cold blocking study (n 5 6/ condition) with unlabeled ABP688. After this experimental validation, rats were pretreated with either NAc (intravenous infusion of 50 mg/kg/h) or MK-801 (0.16 mg/kg; given intraperitoneally); this step was followed by small-animal PET with 11 C-ABP688 (n 5 12) or b-microprobe measurements (n 5 10/condition) of 11 C-ABP688. Time-activity curves were extracted, and the nondisplaceable binding potential (BP ND ) was calculated by use of the simplified reference tissue model with the cerebellum as a reference region. Results: 11 C-ABP688 BP ND measurements were highly reproducible (test-retest), and both small-animal PET and b-microprobes were able to discriminate changes in 11 C-ABP688 binding (cold blocking). The average small-animal PET BP ND measurements in the test experiment for the caudate putamen, frontal cortex, cerebral cortex, hippocampus, and thalamus were 2.58, 1.40, 1.60, 1.86, and 1.09, respectively. However, no significant differences in BP ND measurements were observed with small-animal PET in the test and retest conditions on the one hand and the NAc and MK-801 conditions on the other hand for any of these regions. When b-microprobes were used, the average BP ND in the caudate putamen was 0.94, and no significant changes in the test and MK-801 conditions were observed. Conclusion: Pharmacologic challenges with NAc and MK-801 did not affect the 11 C-ABP688 BP ND in the rat brain. These data suggest that the in vivo affinity of 11 C-ABP688 for binding to an allosteric site of the metabotropic glutamate 5 receptor is not modulated by changes in glutamate levels and that 11 C-ABP688 is not capable of measuring acute fluctuations in endogenous levels of glutamate in vivo in the rat brain.

Metabotropic glutamate receptor 5 binding in patients with obsessive-compulsive disorder

“…Several studies (DeLorenzo et al, 2011;Sandiego et al, 2013;Wyckhuys et al, 2013) addressed the variability of [ 11 C]ABP688 binding. With regards to intrasubject variability's test and re-test studies have not shown significant effects, except one study, which had revealed an unexplained effect (Sandiego et al, 2013).…”

Twenty-four hour quantitative-EEG and in-vivo glutamate biosensor detects activity and circadian rhythm dependent biomarkers of pathogenesis in Mecp2 null mice

“…Sensitivity of the glutamate biosensor in-situ was tested by injecting MK801 intra-peritoneal injection (5 mg/kg), which elicited an immediate (<1 min) and significant rise in the glutamate reading, by the sensor (Figure S1D). MK801 which is an NMDA receptor antagonist is known to induce increases in endogenous glutamate levels (Wyckhuys et al, 2013) and has been used to model various neurologic disorders, such as epilepsy, schizophrenia, and Parkinson disease where abnormal glutamate transmission is hypothesized to be involved (Roenker et al, 2012). …”

Preclinical Evaluation and Quantification of 18F-FPEB as a Radioligand for PET Imaging of the Metabotropic Glutamate Receptor 5

“…Although the cerebellum showed minor radiometabolite presence (,6.5%), the total absolute activity in the cerebellum was low (only 1.5% when compared with the cerebrum). This observation could be explained by incomplete washout of radioactivity in the circulatory system, which can be seen with saline perfusion (20). Quantification of the mGluR5 using 18 F-FPEB is thus feasible when relying on the radiometabolite-corrected ligand input function only.…”