In vitro and In vivo Assessment of Suitable Reference Region and Kinetic Modelling for the mGluR1 Radioligand [11C]ITDM in Mice

Abstract

Purpose: This study aimed at investigating binding specificity, suitability of reference regionbased kinetic modelling, and pharmacokinetics of the metabotropic glutamate receptor 1 (mGluR1) radioligand [ 11 C]ITDM in mice. Procedures: We performed in vivo blocking as well as displacement of [ 11 C]ITDM during positron emission tomography (PET) imaging using the specific mGluR1 antagonist YM-202074. Additionally, we assessed in vitro blocking of [ 3 H]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 [ 11 C]ITDM in the mouse brain. Finally, we also assessed semi-quantitative approaches. Results: In vivo blocking with YM-202074 resulted in a decreased [ 11 C]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 [ 3 H]ITDM binding could be blocked in a dosedependent manner. The volume of distribution (V T) based on the noninvasive IDIF (V T (IDIF)) showed excellent agreement with the V T values based on the metabolite-corrected plasma input function regardless of the metabolite correction (r 2 9 0.943, p G 0.0001). Two-tissue compartmental model (2TCM) was found to be the preferred model and showed optimal agreement with Logan plot (r 2 9 0.960, p G 0.0001). A minimum scan duration of 80 min was required for proper parameter estimation. SUV was not reliable (r 2 = 0.379, p = 0.0011), unlike the SUV ratio to the SUV of the input function, which showed to be a valid approach. Conclusions: No suitable reference region could be identified for [ 11 C]ITDM as strongly supported by in vivo and in vitro evidence of specific binding in all brain regions. However, by

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“…[ 11 C]ITDM synthesis was performed on an automated synthesis module (Carbosynthon I, Comecer, The Netherlands) optimizing the reported procedure [18] to our system as recently described [19]. Average molar activity was 90.1 ± 27.6 GBq/ μmol with radiochemical purity greater than 99%.…”

“…bolus injection of the tracer and were placed on the scanner bed. The whole body was in the PET scanner's field of view to allow the extraction of the image-derived input function (IDIF) from the lumen of the left ventricle of the heart as previously described and validated [19,25]. A monitoring acquisition module (Minerve, France) was used to constantly monitor the respiration of the animal during the entire preparation and scanning period.…”

“…[ 11 C]ITDM image acquisition was performed as previously validated [19]. At the onset of the 90 min dynamic microPET scan, animals were injected with a bolus of [ 11 C]ITDM over a 12 s interval (1 ml/min) using an automated pump (Pump 11 Elite, Harvard Apparatus, USA).…”

“…In order to assess possible genotypic difference in peripheral metabolism, a population-based metabolite analysis was performed in a cohort of WT (n = 15) and HET (n = 15) mice at 0, 5, 15, and 30 min post injection (p.i.). The procedure was as previously described [19]. Briefly, mice were injected with the radioligand via the lateral tail vein, and blood was collected via cardiac puncture.…”

“…The aim of this study was to investigate whether changes in mGluR1 availability occur during disease progression in the same mouse model of HD we used to quantify mGluR5 [17] in order to provide a first evidence before clinical investigation. We performed longitudinal non-invasive PET imaging of mGluR1 at 6, 12, and 16 months of age using the selective radioligand [18], for which we recently validated the pharmacokinetic methodology to perform accurate quantification of mGluR1 availability in the mouse brain [19]. By using the same Q175 mouse model, these findings will offer new insights into the characterization of both mGluR1 and mGluR5 during HD progression.…”