Abstract
PurposeThis study aimed at investigating binding specificity, suitability of reference region-based kinetic modelling, and pharmacokinetics of the metabotropic glutamate receptor 1 (mGluR1) radioligand [11C]ITDM in mice.ProceduresWe performed in vivo blocking as well as displacement of [11C]ITDM during positron emission tomography (PET) imaging using the specific mGluR1 antagonist YM-202074. Additionally, we assessed in vitro blocking of [3H]ITDM at two different doses of YM-202074. As an alternative to reference region models, we validated the use of a noninvasive image-derived input function (IDIF) compared to an arterial input function measured with an invasive arteriovenous (AV) shunt using a population-based curve for radiometabolite correction and characterized the pharmacokinetic modelling of [11C]ITDM in the mouse brain. Finally, we also assessed semi-quantitative approaches.ResultsIn vivo blocking with YM-202074 resulted in a decreased [11C]ITDM binding, ranging from − 35.8 ± 8.0 % in pons to − 65.8 ± 3.0 % in thalamus. Displacement was also markedly observed in all tested regions. In addition, in vitro [3H]ITDM binding could be blocked in a dose-dependent manner. The volume of distribution (VT) based on the noninvasive IDIF (VT (IDIF)) showed excellent agreement with the VT values based on the metabolite-corrected plasma input function regardless of the metabolite correction (r2 > 0.943, p < 0.0001). Two-tissue compartmental model (2TCM) was found to be the preferred model and showed optimal agreement with Logan plot (r2 > 0.960, p < 0.0001). A minimum scan duration of 80 min was required for proper parameter estimation. SUV was not reliable (r2 = 0.379, p = 0.0011), unlike the SUV ratio to the SUV of the input function, which showed to be a valid approach.ConclusionsNo suitable reference region could be identified for [11C]ITDM as strongly supported by in vivo and in vitro evidence of specific binding in all brain regions. However, by applying appropriate kinetic models, [11C]ITDM PET imaging represents a promising tool to visualize mGluR1 in the mouse brain.
Highlights
Glutamate, the major excitatory neurotransmitter in the brain, plays an essential role in a variety of physiological processes
MGluR1 and mGluR5 share a high degree of homology, they are characterized by a distinct cerebral expression pattern, with mGluR5 mainly distributed in the striatum, hippocampus, and cortex, whereas metabotropic glutamate receptors (mGluRs) type 1 (mGluR1) primarily located in the thalamus and in the cerebellum [3, 4]
Since no suitable reference region was present in the mouse brain, we investigated whether an image-derived input function (IDIF) is accurate to circumvent the need for an invasive input function which disables longitudinal studies
Summary
The major excitatory neurotransmitter in the brain, plays an essential role in a variety of physiological processes. The mGluRs of the group I are located post-synaptically, and they include the mGluR type 1 (mGluR1) and type 5 (mGluR5). Both mGluR1 and mGluR5 have been linked to a number of neurological disorders, including epilepsy, stroke, fragile X syndrome, Huntington’s disease, obsessive-compulsive disorder, Alzheimer’s disease, Parkinson’s disease, and drug addiction [2]. Given the relevance of group I mGluRs for the evaluation of potential therapeutic interventions, there is a growing interest for in vivo monitoring of group I mGluRs in the living brain which can be achieved by means of positron emission tomography (PET) imaging. MGluR1 and mGluR5 share a high degree of homology, they are characterized by a distinct cerebral expression pattern, with mGluR5 mainly distributed in the striatum, hippocampus, and cortex, whereas mGluR1 primarily located in the thalamus and in the cerebellum [3, 4]
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