Dataset Information

Kinetic Modelling and Test-Retest Reproducibility for the Dopamine D₁R Radioligand [¹¹C]SCH23390 in Healthy and Diseased Mice.

ABSTRACT:

Purpose

Our 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.

Procedures

Adult 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 (BP_ND). Finally, standardised uptake value ratio (SUVR-1) was assessed as a potential simplified measurement.

Results

For all models, we measured a significant decline in dopamine D₁R density (e.g. SRTM?=?-?38.5?±?5.0 %, p?ND 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 BP_ND measurements were very reproducible with an average test-retest variability below 5 % when using both MRTM and SRTM. Parametric BP_ND maps generated with SRTM were highly reliable, showing nearly perfect agreement to the regional analysis (r²?=?0.99, p?1 with both regional- and voxel-based analyses. SUVR-1 at different time intervals were not sufficiently reliable when compared to BP_ND (r²?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.

SUBMITTER: Bertoglio D

PROVIDER: S-EPMC7910372 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Kinetic Modelling and Test-Retest Reproducibility for the Dopamine D<sub>1</sub>R Radioligand [<sup>11</sup>C]SCH23390 in Healthy and Diseased Mice.

Bertoglio Daniele D Verhaeghe Jeroen J Miranda Alan A Wyffels Leonie L Stroobants Sigrid S Dominguez Celia C Munoz-Sanjuan Ignacio I Skinbjerg Mette M Liu Longbin L Staelens Steven S

Molecular imaging and biology 20201111 2

<h4>Purpose</h4>Our aim in this study was to compare different non-invasive pharmacokinetic models and assess test-retest reproducibility of the radioligand [<sup>11</sup>C]SCH23390 for the quantification of dopamine D<sub>1</sub>-like receptor (D<sub>1</sub>R) in both wild-type (WT) mice and heterozygous (HET) Q175DN mice as Huntington's disease (HD) model.<h4>Procedures</h4>Adult WT (n = 9) and HET (n = 14) mice underwent a 90-min [<sup>11</sup>C]SCH23390 positron emission tomography (PET) sca ...[more]

PMID: 33179158

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Project description:IntroductionAlteration of ?-aminobutyric acid "A" (GABAA) receptor-mediated neurotransmission has been associated with various neurological and psychiatric disorders. [11C]Ro15-4513 is a PET ligand with high affinity for ?5-subunit-containing GABAA receptors, which are highly expressed in limbic regions of the human brain (Sur et al., 1998). We quantified the test-retest reproducibility of measures of [11C]Ro15-4513 binding derived from six different quantification methods (12 variants).MethodsFive healthy males (median age 40 years, range 38-49 years) had a 90-min PET scan on two occasions (median interval 12 days, range 11-30 days), after injection of a median dose of 441 MegaBequerels of [11C]Ro15-4513. Metabolite-corrected arterial plasma input functions (parent plasma input functions, ppIFs) were generated for all scans. We quantified regional binding using six methods (12 variants), some of which were region-based (applied to the average time-activity curve within a region) and others were voxel-based: 1) Models requiring arterial ppIFs - regional reversible compartmental models with one and two tissue compartments (2kbv and 4kbv); 2) Regional and voxelwise Logan's graphical analyses (Logan et al., 1990), which required arterial ppIFs; 3) Model-free regional and voxelwise (exponential) spectral analyses (SA; (Cunningham and Jones, 1993)), which also required arterial ppIFs; 4) methods not requiring arterial ppIFs - voxelwise standardised uptake values (Kenney et al., 1941), and regional and voxelwise simplified reference tissue models (SRTM/SRTM2) using brainstem or alternatively cerebellum as pseudo-reference regions (Lammertsma and Hume, 1996; Gunn et al., 1997). To compare the variants, we sampled the mean values of the outcome parameters within six bilateral, non-reference grey matter regions-of-interest. Reliability was quantified in terms of median absolute percentage test-retest differences (MA-TDs; preferentially low) and between-subject coefficient of variation (BS-CV, preferentially high), both compounded by the intraclass correlation coefficient (ICC). These measures were compared between variants, with particular interest in the hippocampus.ResultsTwo of the six methods (5/12 variants) yielded reproducible data (i.e. MA-TD <10%): regional SRTMs and voxelwise SRTM2s, both using either the brainstem or the cerebellum; and voxelwise SA. However, the SRTMs using the brainstem yielded a lower median BS-CV (7% for regional, 7% voxelwise) than the other variants (8-11%), resulting in lower ICCs. The median ICCs across six regions were 0.89 (interquartile range 0.75-0.90) for voxelwise SA, 0.71 (0.64-0.84) for regional SRTM-cerebellum and 0.83 (0.70-0.86) for voxelwise SRTM-cerebellum. The ICCs for the hippocampus were 0.89 for voxelwise SA, 0.95 for regional SRTM-cerebellum and 0.93 for voxelwise SRTM-cerebellum.ConclusionQuantification of [11C]Ro15-4513 binding shows very good to excellent reproducibility with SRTM and with voxelwise SA which, however, requires an arterial ppIF. Quantification in the ?5 subunit-rich hippocampus is particularly reliable. The very low expression of the ?5 in the cerebellum (Fritschy and Mohler, 1995; Veronese et al., 2016) and the substantial ?1 subunit density in this region may hamper the application of reference tissue methods.

Project description:IntroductionKappa opioid receptors (KOR) are implicated in several brain disorders. In this report, a first-in-human positron emission tomography (PET) study was conducted with the potent and selective KOR agonist tracer, [(11)C]GR103545, to determine an appropriate kinetic model for analysis of PET imaging data and assess the test-retest reproducibility of model-derived binding parameters. The non-displaceable distribution volume (V(ND)) was estimated from a blocking study with naltrexone. In addition, KOR occupancy of PF-04455242, a selective KOR antagonist that is active in preclinical models of depression, was also investigated.MethodsFor determination of a kinetic model and evaluation of test-retest reproducibility, 11 subjects were scanned twice with [(11)C]GR103545. Seven subjects were scanned before and 75 min after oral administration of naltrexone (150 mg). For the KOR occupancy study, six subjects were scanned at baseline and 1.5 h and 8 h after an oral dose of PF-04455242 (15 mg, n=1 and 30 mg, n=5). Metabolite-corrected arterial input functions were measured and all scans were 150 min in duration. Regional time-activity curves (TACs) were analyzed with 1- and 2-tissue compartment models (1TC and 2TC) and the multilinear analysis (MA1) method to derive regional volume of distribution (V(T)). Relative test-retest variability (TRV), absolute test-retest variability (aTRV) and intra-class coefficient (ICC) were calculated to assess test-retest reproducibility of regional VT. Occupancy plots were computed for blocking studies to estimate occupancy and V(ND). The half maximal inhibitory concentration (IC50) of PF-04455242 was determined from occupancies and drug concentrations in plasma. [(11)C]GR103545 in vivo K(D) was also estimated.ResultsRegional TACs were well described by the 2TC model and MA1. However, 2TC VT was sometimes estimated with high standard error. Thus MA1 was the model of choice. Test-retest variability was ~15%, depending on the outcome measure. The blocking studies with naltrexone and PF-04455242 showed that V(T) was reduced in all regions; thus no suitable reference region is available for the radiotracer. V(ND) was estimated reliably from the occupancy plot of naltrexone blocking (V(ND)=3.4±0.9 mL/cm(3)). The IC50 of PF-04455242 was calculated as 55 ng/mL. [(11)C]GR103545 in vivo K(D) value was estimated as 0.069 nmol/L.Conclusions[(11)C]GR103545 PET can be used to image and quantify KOR in humans, although it has slow kinetics and variability of model-derived kinetic parameters is higher than desirable. This tracer should be suitable for use in receptor occupancy studies, particularly those that target high occupancy.

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Dataset Information

Kinetic Modelling and Test-Retest Reproducibility for the Dopamine D₁R Radioligand [¹¹C]SCH23390 in Healthy and Diseased Mice.

Purpose

Procedures

Results

Publications

Kinetic Modelling and Test-Retest Reproducibility for the Dopamine D<sub>1</sub>R Radioligand [<sup>11</sup>C]SCH23390 in Healthy and Diseased Mice.

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Dataset Information

Kinetic Modelling and Test-Retest Reproducibility for the Dopamine D1R Radioligand [11C]SCH23390 in Healthy and Diseased Mice.

Purpose

Procedures

Results

Publications

Kinetic Modelling and Test-Retest Reproducibility for the Dopamine D<sub>1</sub>R Radioligand [<sup>11</sup>C]SCH23390 in Healthy and Diseased Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Kinetic Modelling and Test-Retest Reproducibility for the Dopamine D₁R Radioligand [¹¹C]SCH23390 in Healthy and Diseased Mice.