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首页> 外文期刊>EJNMMI Radiopharmacy and Chemistry >Improved synthesis of [ 18 F] fallypride and characterization of a Huntington’s disease mouse model, zQ175DN KI, using longitudinal PET imaging of D2/D3 receptors
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Improved synthesis of [ 18 F] fallypride and characterization of a Huntington’s disease mouse model, zQ175DN KI, using longitudinal PET imaging of D2/D3 receptors

机译：使用D2 / D3受体的纵向PET成像，改进了[18 F]氟吡脲的合成并鉴定了亨廷顿舞蹈病小鼠模型zQ175DN KI

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Abstract PurposeDopamine receptors are involved in pathophysiology of neuropsychiatric diseases, including Huntington’s disease (HD). PET imaging of dopamine D2 receptors (D2R) in HD patients has demonstrated 40% decrease in D2R binding in striatum, and D2R could be a reliable quantitative target to monitor disease progression. A D2/3R antagonist, [18F] fallypride, is a high-affinity radioligand that has been clinically used to study receptor density and occupancy in neuropsychiatric disorders. Here we report an improved synthesis method for [18F]fallypride. In addition, high molar activity of the ligand has allowed us to apply PET imaging to characterize D2/D3 receptor density in striatum of the recently developed zQ175DN knock-in (KI) mouse model of HD.MethodsWe longitudinally characterized in vivo [18F] fallypride -PET imaging of D2/D3 receptor densities in striatum of 9 and 12?month old wild type (WT) and heterozygous (HET) zQ175DN KI mouse. Furthermore, we verified the D2/D3 receptor density in striatum with [3H] fallypride autoradiography at 12?months of age.ResultsWe implemented an improved synthesis method for [18F] fallypride to yield high molar activity (MA, 298–360?GBq/μmol) and good reproducibility. In the HET zQ175DN KI mice, we observed a significant longitudinal decrease in binding potential (BPND) (30.2%, p ?0.001, 9?months of age and 51.6%, p??0.001, 12?months of age) compared to WT littermates. No mass effect was observed when the MA of [18?100?GBq/μmol at the time of injection. Furthermore, the decrease of D2/D3 receptor density in striatum in HET zQ175DN KI was consistent using [3H] fallypride autoradiography.ConclusionsWe observed a significant decrease in D2/D3R receptor densities in the striatum of HET zQ175DN KI mice compared to WT mice at 9 and 12?months of age. These results are in line with clinical findings in HD patients, suggesting [18F] fallypride PET imaging has potential as a quantitative translational approach to monitor disease progression in preclinical studies.
机译：摘要目的多巴胺受体参与神经精神疾病的病理生理，包括亨廷顿氏病（HD）。 HD患者的多巴胺D2受体（D2R）的PET成像显示纹状体中D2R结合减少40％，D2R可能是监测疾病进展的可靠定量目标。 D2 / 3R拮抗剂[18F] fallypride是一种高亲和力放射性配体，已在临床上用于研究神经精神疾病的受体密度和占有率。在这里，我们报告了一种改进的[18F]氟脲嘧啶合成方法。此外，配体的高摩尔活性使我们能够应用PET成像来表征最近开发的HD zQ175DN敲入（KI）小鼠模型的纹状体中的D2 / D3受体密度。方法我们纵向表征了体内[18F]氟脲-PET成像的9和12月龄野生型（WT）和杂合型（HET）zQ175DN KI小鼠纹状体中的D2 / D3受体密度。此外，我们用[3H]氟吡胺放射自显影在12个月大时验证了纹状体中D2 / D3受体的密度。结果我们实施了一种改进的[18F]氟吡脲合成方法，以产生高的摩尔活性（MA，298-360？GBq / μmol）和良好的重现性。在HET zQ175DN KI小鼠中，我们观察到结合电位（BPND）的纵向显着降低（30.2％，p <？0.001，9个月大和51.6％，p 0.001，12个月大）。 WT野生动物。注射时的MA为[18？100？GBq /μmol]时，未观察到质量效应。此外，使用[3H]法进行放射自显影，HET zQ175DN KI纹状体中D2 / D3受体密度的下降是一致的。和12个月大。这些结果与HD患者的临床发现相吻合，表明[18F]法替利PET成像作为临床研究中监测疾病进展的定量转化方法具有潜力。

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