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.
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。