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.

UNLABELLED 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 β-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 = 3) and after a selected treatment (n = 3); second, a test-retest (n = 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 β-microprobe cold blocking study (n = 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 = 12) or β-microprobe measurements (n = 10/condition) of (11)C-ABP688. Time-activity curves were extracted, and the nondisplaceable binding potential (BPND) was calculated by use of the simplified reference tissue model with the cerebellum as a reference region. RESULTS (11)C-ABP688 BPND measurements were highly reproducible (test-retest), and both small-animal PET and β-microprobes were able to discriminate changes in (11)C-ABP688 binding (cold blocking). The average small-animal PET BPND 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 BPND 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 β-microprobes were used, the average BPND 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 BPND 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.