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Title
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In vitro and In vivo assessment of suitable reference region and kinetic modelling for the mGluR1 radioligand ITDM in mice
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Author
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Abstract
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| Purpose This study aimed at investigating binding specificity, suitability of reference region-based kinetic modelling, and pharmacokinetics of the metabotropic glutamate receptor 1 (mGluR1) radioligand [C-11]ITDM in mice. Procedures We performed in vivo blocking as well as displacement of [C-11]ITDM during positron emission tomography (PET) imaging using the specific mGluR1 antagonist YM-202074. Additionally, we assessed in vitro blocking of [H-3]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 [C-11]ITDM in the mouse brain. Finally, we also assessed semi-quantitative approaches. Results In vivo blocking with YM-202074 resulted in a decreased [C-11]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 [H-3]ITDM binding could be blocked in a dose-dependent 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) > 0.943, p < 0.0001). Two-tissue compartmental model (2TCM) was found to be the preferred model and showed optimal agreement with Logan plot (r(2) > 0.960, p < 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 [C-11]ITDM as strongly supported by in vivo and in vitro evidence of specific binding in all brain regions. However, by applying appropriate kinetic models, [C-11]ITDM PET imaging represents a promising tool to visualize mGluR1 in the mouse brain. |
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Language
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English
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Source (journal)
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Molecular imaging and biology. - New York, N.Y., 2002, currens
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Publication
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New york
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Springer
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2019
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ISSN
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1536-1632
[print]
1860-2002
[online]
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DOI
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10.1007/S11307-019-01435-1
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Volume/pages
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10 p.
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ISI
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000499965700005
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Pubmed ID
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31792838
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Full text (Publisher's DOI)
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Full text (open access)
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