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Mol Imaging Biol. 2019 Dec 2. doi: 10.1007/s11307-019-01435-1. [Epub ahead of print]

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

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Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, Wilrijk, Belgium.
Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium.
CHDI Management/CHDI Foundation, Los Angeles, CA, USA.
Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, Wilrijk, Belgium.



This 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.


We 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.


In 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.


No 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.


Arteriovenous shunt; Kinetic modelling; Mouse; PET; Preclinical imaging; Reference region; [11C]ITDM; mGluR1


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