Imaging in Vivo Glutamate Fluctuations with [¹¹C]ABP688: A GLT-1 Challenge with Ceftriaxone

Abstract

Molecular imaging offers unprecedented opportunities for investigating dynamic changes underlying neuropsychiatric conditions. Here, we evaluated whether [11C]ABP688, a positron emission tomography (PET) ligand that binds to the allosteric site of the metabotropic glutamate receptor type 5 (mGluR5), is sensitive to glutamate fluctuations after a pharmacological challenge. For this, we used ceftriaxone (CEF) administration in rats, an activator of the GLT-1 transporter (EAAT2), which is known to decrease extracellular levels of glutamate. MicroPET [11C]ABP688 dynamic acquisitions were conducted in rats after a venous injection of either saline (baseline) or CEF 200 mg/kg (challenge). Binding potentials (BPND) were obtained using the simplified reference tissue method. Between-condition statistical parametric maps indicating brain regions showing the highest CEF effects guided placement of microdialysis probes for subsequent assessment of extracellular levels of glutamate. The CEF administration increased [11C]ABP688 BPND in the thalamic ventral anterior (VA) nucleus bilaterally. Subsequent microdialysis assessment revealed declines in extracellular glutamate concentrations in the VA. The present results support the concept that availability of mGluR5 allosteric binding sites is sensitive to extracellular concentrations of glutamate. This interesting property of mGluR5 allosteric binding sites has potential applications for assessing the role of glutamate in the pathogenesis of neuropsychiatric conditions.

Circadian variation of metabotropic glutamate receptor 5 availability in the rat brain

“…Some experiments in non‐human primates, using pharmacologically elevated glutamate levels by n‐acetylcysteine, indicated displacement of ABP688 binding (Miyake et al ., ; Sandiego et al ., ). However, these findings could not be replicated in rats (Wyckhuys et al ., ), while a pharmacological reduction of glutamate levels by activation of the GLT‐1 transporter in rats resulted in an increase in specific binding of ABP688 (Zimmer et al ., ). The pattern of glutamatergic receptor expression observed in the study at hand (nadir of mGluR5 at the end of the dark phase) is contrary to the circadian changes of its neurotransmitter levels measured with microdialysis.…”

In vivo metabotropic glutamate receptor type 5 abnormalities localize the epileptogenic zone in mesial temporal lobe epilepsy

“…The precise nature of the allosteric binding site reductions remains elusive and might include receptor internalization, conformational changes driven by tissue hyperexcitability, or simply excessive extracellular glutamate levels present in the EZ . Whereas binding properties of [ 11 C]ABP688 to the transmembrane allosteric site are sensitive to changes in mGluR5 tertiary or quaternary conformations, measures conducted with immunohistochemistry remain unaffected by in vivo receptor conformations.…”

“…[ 11 C]ABP688 binding might also be highly influenced by levels of extracellular glutamate. Experiments manipulating extracellular concentrations of glutamate using pharmacological agents in rats, nonhuman primates, and humans have demonstrated an inverse correlation between [ 11 C]ABP688 binding and glutamate levels . Glutamate binding to the orthosteric site can induce a conformational change in mGluR5 such that [ 11 C]ABP688’s affinity to the allosteric site is reduced .…”

Test–retest variability of [11C]ABP688 estimates of metabotropic glutamate receptor subtype 5 availability in humans

“…While results in clinical populations are commonly interpreted to reflect changes in receptor density, drug challenge studies in animals and humans have raised the possibility that [ 11 C]ABP688 may also be sensitive to changes in extracellular glutamate levels. In humans, lower [ 11 C]ABP688 binding is seen following administration of ketamine, known to increase glutamate levels (DeLorenzo et al, ; Esterlis et al, ), while binding levels increase in rats after administration of ceftriaxone, which decreases glutamate (Zimmer et al, ). Because [ 11 C]ABP688 binds at an allosteric site, this would not be caused by direct competition between glutamate and the radiotracer; rather, increased glutamate levels might instead alter affinity at the allosteric site or induce receptor internalization.…”