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

Daniele Bertoglio; Jeroen Verhaeghe; Špela Korat; Alan Miranda; Leonie Wyffels; Sigrid Stroobants; Ladislav Mrzljak; Celia Dominguez; Longbin Liu; Mette Skinbjerg; Ignacio Munoz-Sanjuan; Steven Staelens

doi:10.1007/s11307-019-01435-1

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

Mol Imaging Biol. 2020 Aug;22(4):854-863. doi: 10.1007/s11307-019-01435-1.

Authors

Affiliations

¹ Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, Wilrijk, Belgium.
² Department of Nuclear Medicine, Antwerp University Hospital, Edegem, Belgium.
³ CHDI Management/CHDI Foundation, Los Angeles, CA, USA.
⁴ Molecular Imaging Center Antwerp (MICA), Faculty of Medicine and Health Sciences, University of Antwerp, Universiteitsplein 1, Wilrijk, Belgium. steven.staelens@uantwerpen.be.

Abstract

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 [¹¹C]ITDM in mice.

Procedures: 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.

Results: 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 (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 (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.

Conclusions: 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.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autoradiography
Brain / pathology
Carbon Radioisotopes / chemistry*
Carbon Radioisotopes / pharmacokinetics
Kinetics
Ligands
Male
Mice, Inbred C57BL
Radiopharmaceuticals / chemistry*
Receptors, Metabotropic Glutamate / metabolism*
Reference Standards
Time Factors

Substances

Carbon Radioisotopes
Carbon-11
Ligands
Radiopharmaceuticals
Receptors, Metabotropic Glutamate
metabotropic glutamate receptor type 1