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.

中文翻译：

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多巴胺 D 1 R 放射性配体 [ 11 C]SCH23390 在健康和患病小鼠中的动力学建模和测试 - 重新测试重现性

目的

我们在本研究的目的是比较不同的非侵入性的药物代谢动力学模型和评估放射性配体的重测再现性[ ¹¹ C] SCH23390用于定量多巴胺d ₁状受体（d ₁ R）在野生型（WT ) 小鼠和杂合 (HET) Q175DN 小鼠作为亨廷顿病 (HD) 模型。

程序

成年 WT ( n  = 9) 和 HET ( n  = 14) 小鼠接受了 90 分钟 [ ¹¹ C]SCH23390 正电子发射断层扫描 (PET) 扫描，然后进行计算机断层扫描 (CT) 以评估健康和疾病条件下的药代动力学模型。此外，5 只 WT 小鼠和 7 只 HET 动物接受了第二次 [ ¹¹ C]SCH23390 PET 扫描以进行测试-再测试的重现性。使用纹状体作为富含受体的区域和小脑作为无受体（参考）的简化参考组织模型 (SRTM)、多线性参考组织模型 (MRTM) 和 Logan 参考组织模型 (Logan Ref) 的并行评估进行区域以定义基于区域和体素的结合电位量化的最合适方法（BP _ND）。最后，标准化吸收值比 (SUVR-1) 被评估为潜在的简化测量。

结果

对于所有模型，我们测量 到 HET 小鼠中多巴胺 D ₁ R 密度（例如SRTM = - 38.5 ± 5.0 %，p < 0.0001）与 WT 同窝仔鼠相比显着下降。缩短90分钟的扫描持续时间造成了大低估纹状体的BP _ND在两个野生型小鼠（SRTM 60分钟： - 17.7±2.8％，p  = 0.0078）和病变HET（SRTM 60分钟： - 13.1±4.1％，p  = 0.0001）。当同时使用 MRTM 和 SRTM 时，纹状体BP _ND测量的重现性非常好，平均测试-再测试变异性低于 5%。参数化BP _ND使用 SRTM 生成的地图高度可靠，显示出与区域分析几乎完全一致（r ²  = 0.99，p  < 0.0001）。最后，SRTM通过基于区域和基于体素的分析为相对示踪剂传递R ₁提供了最准确的估计。与BP _ND相比，不同时间间隔的 SUVR-1 不够可靠（r ²  < 0.66）。

结论

建议进行 90 分钟采集并使用 SRTM 进行药代动力学建模。[ ¹¹ C]SCH23390 PET 成像展示了研究精神和神经疾病模型中多巴胺 D ₁ R 密度的最佳特征，如 HD 的 Q175DN 小鼠模型所示。