Preclinical evaluation of [¹⁸F]SYN1 and [¹⁸F]SYN2, novel radiotracers for PET myocardial perfusion imaging.

IF 3.1 3区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

EJNMMI Research Pub Date : 2024-07-08 DOI:10.1186/s13550-024-01122-5

Seweryn Krajewski, Lukasz Steczek, Karina Gotowicz, Urszula Karczmarczyk, Joanna Towpik, Ewa Witkowska-Patena, Krzysztof Łyczko, Maciej Mazur, Przemysław Kozanecki, Joanna Włostowska, Juhani Knuuti, Mirosław Dziuk, Piotr Garnuszek, Cezary Kozanecki

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引用次数: 0

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.

Conclusion: [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.

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用于 PET 心肌灌注成像的新型放射性同位素 [18F]SYN1 和 [18F]SYN2 的临床前评估。

背景：目前，正电子发射断层扫描（PET）已成为冠心病心肌灌注成像（MPI）的一种成熟诊断方法，而冠心病是导致全球死亡的主要原因。现有的示踪剂存在一些局限性，因此，18F 标记的示踪剂目前需求量很大。在正常 Wistar 大鼠身上进行的临床前研究旨在描述两种潜在的新型放射性示踪剂--[18F]SYN1 和 [18F]SYN2，以评估哪一种更适合作为 PET MPI 心脏示踪剂：结果：动态 microPET 图像显示，两种示踪剂都能快速摄取心肌。然而，[18F]SYN2 的摄取率更高，也更稳定，平均标准化摄取值为 3.8。生物分布研究证实，与[18F]SYN1（15 分钟内为 1.84%ID/g，6 小时内为 0.32%ID/g）相比，[18F]SYN2 在心肌中的摄取率较高且稳定（15 分钟内为 3.02%ID/g，6 小时内为 2.79%ID/g）。剂量测定研究确定的关键器官是小肠和肾脏。据估计，[18F]SYN1 的人体有效剂量为 0.00714 mSv/MBq，[18F]SYN2 为 0.0109 mSv/MBq。2 毫克/千克的测试剂量水平被认为是这两种候选物质的无观测不良效应水平（NOAEL）。[18F]SYN2取得了较好的结果，因此只对该示踪剂进行了进一步的临床前研究。放射性配体结合试验显示，在 68 项试验中，有 3 项有明显反应：毒蕈碱乙酰胆碱 M1 和 M2 受体以及钾通道 hERG。该化合物主要通过 N-脱烷基氧化作用进行代谢，而氟取代基则未从分子中分离出来：结论：[18F]SYN2 显示出良好的药效学和药代动力学特征，可在 microPET 中清晰显示心脏。在对正常大鼠进行的研究中，该化合物的耐受性良好，辐射量适中。研究结果鼓励在临床研究中进一步探索[18F]SYN2。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EJNMMI Research RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING&nb-

CiteScore

5.90

自引率

3.10%

发文量

审稿时长

13 weeks

期刊介绍： EJNMMI Research publishes new basic, translational and clinical research in the field of nuclear medicine and molecular imaging. Regular features include original research articles, rapid communication of preliminary data on innovative research, interesting case reports, editorials, and letters to the editor. Educational articles on basic sciences, fundamental aspects and controversy related to pre-clinical and clinical research or ethical aspects of research are also welcome. Timely reviews provide updates on current applications, issues in imaging research and translational aspects of nuclear medicine and molecular imaging technologies. The main emphasis is placed on the development of targeted imaging with radiopharmaceuticals within the broader context of molecular probes to enhance understanding and characterisation of the complex biological processes underlying disease and to develop, test and guide new treatment modalities, including radionuclide therapy.