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Abstract：
BACKGROUND: Positron emission tomography (PET) is now an established diagnostic method for myocardial perfusion imaging (MPI) in coronary artery disease, which is the main cause of death globally. The available tracers show several limitations, therefore, the 18F-labelled tracer is in high demand nowadays. The preclinical studies on normal Wistar rats aimed to characterise two potential, novel radiotracers, [18F]SYN1 and [18F]SYN2, to evaluate which is a better candidate for PET MPI cardiotracer.
RESULTS: The dynamic microPET images showed rapid myocardial uptake for both tracers. However, the uptake was higher and also stable for [18F]SYN2, with an average standardized uptake value of 3.8. The biodistribution studies confirmed that [18F]SYN2 uptake in the cardiac muscle was high and stable (3.02%ID/g at 15 min and 2.79%ID/g at 6 h) compared to [18F]SYN1 (1.84%ID/g at 15 min and 0.32%ID/g at 6 h). The critical organs determined in dosimetry studies were the small intestine and the kidneys. The estimated effective dose for humans was 0.00714 mSv/MBq for [18F]SYN1 and 0.0109 mSv/MBq for [18F]SYN2. The tested dose level of 2 mg/kg was considered to be the No Observed Adverse Effect Level (NOAEL) for both candidates. The better results were achieved for [18F]SYN2, therefore, further preclinical studies were conducted only for this tracer. Radioligand binding assays showed significant responses in 3 from 68 assays: muscarinic acetylcholine M1 and M2 receptors and potassium channel hERG. The compound was mostly metabolised via an oxidative N-dealkylation, while the fluor substituent was not separated from the molecule.
CONCLUSIONS: [18F]SYN2 showed a favourable pharmacodynamic and pharmacokinetic profile, which enabled a clear visualization of the heart in microPET. The compound was well-tolerated in studies in normal rats with moderate radiation exposure. The results encourage further exploration of [18F]SYN2 in clinical studies.
RESULTS: The dynamic microPET images showed rapid myocardial uptake for both tracers. However, the uptake was higher and also stable for [18F]SYN2, with an average standardized uptake value of 3.8. The biodistribution studies confirmed that [18F]SYN2 uptake in the cardiac muscle was high and stable (3.02%ID/g at 15 min and 2.79%ID/g at 6 h) compared to [18F]SYN1 (1.84%ID/g at 15 min and 0.32%ID/g at 6 h). The critical organs determined in dosimetry studies were the small intestine and the kidneys. The estimated effective dose for humans was 0.00714 mSv/MBq for [18F]SYN1 and 0.0109 mSv/MBq for [18F]SYN2. The tested dose level of 2 mg/kg was considered to be the No Observed Adverse Effect Level (NOAEL) for both candidates. The better results were achieved for [18F]SYN2, therefore, further preclinical studies were conducted only for this tracer. Radioligand binding assays showed significant responses in 3 from 68 assays: muscarinic acetylcholine M1 and M2 receptors and potassium channel hERG. The compound was mostly metabolised via an oxidative N-dealkylation, while the fluor substituent was not separated from the molecule.
CONCLUSIONS: [18F]SYN2 showed a favourable pharmacodynamic and pharmacokinetic profile, which enabled a clear visualization of the heart in microPET. The compound was well-tolerated in studies in normal rats with moderate radiation exposure. The results encourage further exploration of [18F]SYN2 in clinical studies.
摘要：
背景：正电子发射断层扫描（PET）现在是冠状动脉疾病中心肌灌注显像（MPI）的既定诊断方法，这是全球死亡的主要原因。可用的示踪剂显示出一些局限性，因此,18F标记的示踪剂现在需求量很大。对正常Wistar大鼠的临床前研究旨在表征两种潜能，新颖的放射性示踪剂，[18F]SYN1和[18F]SYN2，以评估哪个是PETMPI心脏示踪剂的更好候选者。
结果：动态microPET图像显示两种示踪剂的心肌摄取迅速。然而,[18F]SYN2的摄取较高且稳定,平均标准化摄取值为3.8.生物分布研究证实，与[18F]SYN1（1.84％ID/g在15分钟和0.32％ID/g在6小时）相比，心肌中的[18F]SYN2摄取高且稳定（15分钟为3.02％ID/g，6小时为2.79％ID/g）。在剂量学研究中确定的关键器官是小肠和肾脏。人的估计有效剂量为[18F]SYN1的0.00714mSv/MBq和[18F]SYN2的0.0109mSv/MBq。2mg/kg的测试剂量水平被认为是两种候选物的未观察到的不良反应水平(NOAEL)。[18F]SYN2取得了较好的结果，因此，仅对该示踪剂进行了进一步的临床前研究.放射性配体结合测定显示来自68个测定的3个显著响应:毒蕈碱乙酰胆碱M1和M2受体和钾通道hERG。该化合物主要通过氧化N-脱烷基化代谢，而氟取代基未与分子分离。
结论：[18F]SYN2表现出良好的药效学和药代动力学特征，这使得在microPET中可以清晰地看到心脏。在具有中等辐射暴露的正常大鼠的研究中,该化合物具有良好的耐受性。该结果鼓励在临床研究中进一步探索[18F]SYN2。
结果：动态microPET图像显示两种示踪剂的心肌摄取迅速。然而,[18F]SYN2的摄取较高且稳定,平均标准化摄取值为3.8.生物分布研究证实，与[18F]SYN1（1.84％ID/g在15分钟和0.32％ID/g在6小时）相比，心肌中的[18F]SYN2摄取高且稳定（15分钟为3.02％ID/g，6小时为2.79％ID/g）。在剂量学研究中确定的关键器官是小肠和肾脏。人的估计有效剂量为[18F]SYN1的0.00714mSv/MBq和[18F]SYN2的0.0109mSv/MBq。2mg/kg的测试剂量水平被认为是两种候选物的未观察到的不良反应水平(NOAEL)。[18F]SYN2取得了较好的结果，因此，仅对该示踪剂进行了进一步的临床前研究.放射性配体结合测定显示来自68个测定的3个显著响应:毒蕈碱乙酰胆碱M1和M2受体和钾通道hERG。该化合物主要通过氧化N-脱烷基化代谢，而氟取代基未与分子分离。
结论：[18F]SYN2表现出良好的药效学和药代动力学特征，这使得在microPET中可以清晰地看到心脏。在具有中等辐射暴露的正常大鼠的研究中,该化合物具有良好的耐受性。该结果鼓励在临床研究中进一步探索[18F]SYN2。
