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 < 0.0001) in HET mice compared to WT littermates. Shortening the 90-min scan duration resulted in large underestimation of striatal BP_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 < 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 BP_ND (r² < 0.66). Conclusions Ninety-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.