Kinetic Modelling and Test\u2013Retest Reproducibility for the Dopamine D1R Radioligand [11C]SCH23390 in Healthy and Diseased Mice

Daniele Bertoglio,Ignacio Munoz-Sanjuan,Mette Skinbjerg,Celia Dominguez,Sigrid Stroobants,Leonie Wyffels,Steven Staelens,Jeroen Verhaeghe,Alan Miranda,Longbin Liu

doi:10.1007/s11307-020-01561-1

Daniele Bertoglio, Ignacio Munoz-Sanjuan + Show 8 more

Open Access

https://doi.org/10.1007/s11307-020-01561-1

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Abstract

PurposeOur aim in this study was to compare different non-invasive pharmacokinetic models and assess test–retest reproducibility of the radioligand [11C]SCH23390 for the quantification of dopamine D1-like receptor (D1R) in both wild-type (WT) mice and heterozygous (HET) Q175DN mice as Huntington’s disease (HD) model.ProceduresAdult WT (n = 9) and HET (n = 14) mice underwent a 90-min [11C]SCH23390 positron emission tomography (PET) scan followed by computed tomography (CT) to evaluate the pharmacokinetic modelling in healthy and diseased conditions. Additionally, 5 WT mice and 7 HET animals received a second [11C]SCH23390 PET scan for test–retest reproducibility. Parallel assessment of the simplified reference tissue model (SRTM), the multilinear reference tissue model (MRTM) and the Logan reference tissue model (Logan Ref) using the striatum as a receptor-rich region and the cerebellum as a receptor-free (reference) region was performed to define the most suitable method for regional- and voxel-based quantification of the binding potential (BPND). Finally, standardised uptake value ratio (SUVR-1) was assessed as a potential simplified measurement.ResultsFor all models, we measured a significant decline in dopamine D1R density (e.g. SRTM = − 38.5 ± 5.0 %, p < 0.0001) in HET mice compared to WT littermates. Shortening the 90-min scan duration resulted in large underestimation of striatal BPND in both WT mice (SRTM 60 min: − 17.7 ± 2.8 %, p = 0.0078) and diseased HET (SRTM 60 min: − 13.1 ± 4.1 %, p = 0.0001). Striatal BPND measurements were very reproducible with an average test–retest variability below 5 % when using both MRTM and SRTM. Parametric BPND maps generated with SRTM were highly reliable, showing nearly perfect agreement to the regional analysis (r2 = 0.99, p < 0.0001). Finally, SRTM provided the most accurate estimate for relative tracer delivery R1 with both regional- and voxel-based analyses. SUVR-1 at different time intervals were not sufficiently reliable when compared to BPND (r2 < 0.66).ConclusionsNinety-minute acquisition and the use of SRTM for pharmacokinetic modelling is recommended. [11C]SCH23390 PET imaging demonstrates optimal characteristics for the study of dopamine D1R density in models of psychiatric and neurological disorders as exemplified in the Q175DN mouse model of HD.

Highlights

Dopamine D1-like receptors (D1R) are post-synaptic G protein-coupled receptors widely distributed in the central nervous system [1]
Since the performance of a radioligand can vary with receptor density, we focused on the methodological characterisation of [11C]SCH23390 positron emission tomography (PET) imaging using both wild-type (WT)
Based on our previous observation that the use of magnetic resonance imaging (MRI) templates for spatial normalisation and volumes of interest (VOIs) definition improves the accuracy of the regional quantification of PET data with focal uptake, an MRI template for each genotype was obtained from another independent cohort of age-matched Q175DN WT (n = 6) and HET (n = 6) mice

Summary

Introduction

Dopamine D1-like receptors (D1R) are post-synaptic G protein-coupled receptors widely distributed in the central nervous system [1]. They are primarily expressed in the caudate and putamen nucleus with lower levels in limbic and cortical structures [2, 3]. Dopamine D1R is markedly reduced in individuals with HD, as demonstrated in vivo using [11C]SCH23390 PET imaging [19,20,21,22] This phenotype was confirmed in vitro in the transgenic R6/2 and BACHD mouse models of HD using [3H]SCH23390 autoradiography [23] as well as in vivo in the knock-in Q175DN mouse model of HD using [11C]NNC-112 PET imaging [24]. Since the performance of a radioligand can vary with receptor density, we focused on the methodological characterisation of [11C]SCH23390 PET imaging using both wild-type (WT)

Methods

Results

Conclusion