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Abstract：
BACKGROUND: N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (FP-CIT), the representative cocaine derivative used in dopamine transporter imaging, is a promising biomarker, as it reflects the severity of Parkinson\'s disease (PD). 123I- and 18F-labeled FP-CIT has been used for PD diagnosis. However, preclinical studies evaluating [18F]FP-CIT as a potential diagnostic biomarker are scarce. Among translational research advancements from bench to bedside, translating preclinical findings into clinical practice is one-directional. The aim of this study is to employ a circular approach, beginning back from the preclinical stage, progressing to the supplementation of [18F]FP-CIT, and subsequently returning to clinical application. We investigated the pharmacokinetic properties of [18F]FP-CIT and its efficacy for PD diagnosis using murine models.
RESULTS: Biodistribution, metabolite and excretion analyses were performed in mice and PD models were induced in rats using 6-hydroxydopamine (6-OHDA). The targeting efficiency of [18F]FP-CIT for the dopamine receptor was assessed through animal PET/CT imaging. Subsequently, correlation analysis was conducted between animal PET/CT imaging results and immunohistochemistry (IHC) targeting tyrosine hydroxylase. Rapid circulation was confirmed after [18F]FP-CIT injection. [18F]FP-CIT reached the highest uptake of 23.50 ± 12.46%ID/g in the striatum 1 min after injection, and it was rapidly excreted within 60 min. The major metabolic organs of [18F]FP-CIT were confirmed to be the intestines, liver, and kidneys. Its uptake in the intestine was approximately 5% ID/g. The uptake in the liver gradually increased, with excretion beginning after reaching a maximum after 60 min. The kidneys exhibited rapid elimination after 10 min. In the excretion study, rapid elimination was verified, with 21.46 ± 9.53% of the compound excreted within a 6 h period. Additionally, the efficacy of [18F]FP-CIT PET was demonstrated in the PD model, with a high correlation with IHC for both the absolute value (R = 0.803, p = 0.0017) and the ratio value (R = 0.973, p = 0.0011).
CONCLUSIONS: This study fills the gap regarding insufficient preclinical studies on [18F]FP-CIT, including its ADME, metabolites, and efficiency. The pharmacological results, including accurate diagnosis, rapid circulation, and [18F]FP-CIT excretion, provide complementary evidence that [18F]FP-CIT can be used safely and efficiently to diagnose PD in clinics, although it is already used in clinics.
RESULTS: Biodistribution, metabolite and excretion analyses were performed in mice and PD models were induced in rats using 6-hydroxydopamine (6-OHDA). The targeting efficiency of [18F]FP-CIT for the dopamine receptor was assessed through animal PET/CT imaging. Subsequently, correlation analysis was conducted between animal PET/CT imaging results and immunohistochemistry (IHC) targeting tyrosine hydroxylase. Rapid circulation was confirmed after [18F]FP-CIT injection. [18F]FP-CIT reached the highest uptake of 23.50 ± 12.46%ID/g in the striatum 1 min after injection, and it was rapidly excreted within 60 min. The major metabolic organs of [18F]FP-CIT were confirmed to be the intestines, liver, and kidneys. Its uptake in the intestine was approximately 5% ID/g. The uptake in the liver gradually increased, with excretion beginning after reaching a maximum after 60 min. The kidneys exhibited rapid elimination after 10 min. In the excretion study, rapid elimination was verified, with 21.46 ± 9.53% of the compound excreted within a 6 h period. Additionally, the efficacy of [18F]FP-CIT PET was demonstrated in the PD model, with a high correlation with IHC for both the absolute value (R = 0.803, p = 0.0017) and the ratio value (R = 0.973, p = 0.0011).
CONCLUSIONS: This study fills the gap regarding insufficient preclinical studies on [18F]FP-CIT, including its ADME, metabolites, and efficiency. The pharmacological results, including accurate diagnosis, rapid circulation, and [18F]FP-CIT excretion, provide complementary evidence that [18F]FP-CIT can be used safely and efficiently to diagnose PD in clinics, although it is already used in clinics.
摘要：
背景：N-（3-氟丙基）-2β-羧基甲氧基-3β-（4-碘苯基）去甲托烷（FP-CIT），用于多巴胺转运蛋白成像的代表性可卡因衍生物，是一种有前途的生物标志物，因为它反映了帕金森病（PD）的严重程度。123I和18F标记的FP-CIT已用于PD诊断。然而,评估[18F]FP-CIT作为潜在诊断生物标志物的临床前研究很少。在从长凳到床边的转化研究进展中，将临床前发现转化为临床实践是单向的。这项研究的目的是采用循环方法，从临床前阶段开始，正在补充[18F]FP-CIT，随后恢复临床应用。我们使用小鼠模型研究了[18F]FP-CIT的药代动力学特性及其对PD诊断的功效。
结果：生物分布，在小鼠中进行代谢物和排泄分析,并在大鼠中使用6-羟基多巴胺(6-OHDA)诱导PD模型.通过动物PET/CT成像评估[18F]FP-CIT对多巴胺受体的靶向效率。随后，对动物PET/CT显像结果与靶向酪氨酸羟化酶的免疫组织化学(IHC)结果进行相关性分析。[18F]FP-CIT注射后确认快速循环。注射后1分钟，[18F]FP-CIT在纹状体中达到23.50±12.46％ID/g的最高摄取，并在60分钟内迅速排出体外。[18F]FP-CIT的主要代谢器官被证实是肠道，肝脏,还有肾脏.其在肠中的摄取为约5%ID/g。在肝脏中的摄取逐渐增加，在60分钟后达到最大值后开始排泄。10分钟后肾脏表现出快速消除。在排泄研究中，快速消除得到验证，在6小时内排泄了21.46±9.53％的化合物。此外,在PD模型中证明了[18F]FP-CITPET的功效，绝对值（R=0.803，p=0.0017）和比值（R=0.973，p=0.0011）与IHC高度相关。
结论：这项研究填补了[18F]FP-CIT临床前研究不足的空白，包括它的ADME,代谢物，和效率。药理学结果，包括准确的诊断,快速循环，和[18F]FP-CIT排泄，提供补充证据证明[18F]FP-CIT可以安全有效地用于临床诊断PD，虽然它已经在诊所使用。
结果：生物分布，在小鼠中进行代谢物和排泄分析,并在大鼠中使用6-羟基多巴胺(6-OHDA)诱导PD模型.通过动物PET/CT成像评估[18F]FP-CIT对多巴胺受体的靶向效率。随后，对动物PET/CT显像结果与靶向酪氨酸羟化酶的免疫组织化学(IHC)结果进行相关性分析。[18F]FP-CIT注射后确认快速循环。注射后1分钟，[18F]FP-CIT在纹状体中达到23.50±12.46％ID/g的最高摄取，并在60分钟内迅速排出体外。[18F]FP-CIT的主要代谢器官被证实是肠道，肝脏,还有肾脏.其在肠中的摄取为约5%ID/g。在肝脏中的摄取逐渐增加，在60分钟后达到最大值后开始排泄。10分钟后肾脏表现出快速消除。在排泄研究中，快速消除得到验证，在6小时内排泄了21.46±9.53％的化合物。此外,在PD模型中证明了[18F]FP-CITPET的功效，绝对值（R=0.803，p=0.0017）和比值（R=0.973，p=0.0011）与IHC高度相关。
结论：这项研究填补了[18F]FP-CIT临床前研究不足的空白，包括它的ADME,代谢物，和效率。药理学结果，包括准确的诊断,快速循环，和[18F]FP-CIT排泄，提供补充证据证明[18F]FP-CIT可以安全有效地用于临床诊断PD，虽然它已经在诊所使用。
