1 Central Animal Laboratory, University of Turku, Turku, Finland.
2 Turku PET Centre, University of Turku, Turku, Finland.
Int J Toxicol. 2019 Jan/Feb;38(1):4-11. doi: 10.1177/1091581818821606. Epub 2019 Jan 20.
The peptide-based radioactive compound [Ga]Ga-DOTA-Siglec-9 is a novel agent for imaging of inflammation with positron emission tomography. The drug target of [Ga]Ga-DOTA-Siglec-9 is vascular adhesion protein 1. Previous studies have obtained promising results with [Ga]Ga-DOTA-Siglec-9 in experimental animals. However, before taking this novel imaging agent into clinical trials, safety and toxicological studies need to be performed with the nonradioactive precursor compound DOTA-Siglec-9. This extended single-dose toxicity study was designed to provide information on the major toxic effects of DOTA-Siglec-9 and to indicate possible target organs after a single intravenous (iv) injection in rats. The study was performed using 60 adult Hsd: Sprague Dawley rats and included a control group and a treatment group to investigate the toxicity of DOTA-Siglec-9 solution at a final concentration of 0.2 mg/mL after a single iv injection of 582 µg/kg. The maximum dose tested was 1,000-fold the clinical dose on a mg/kg basis as indicated in European Medicines Agency International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use guideline M3(R2). The planned human clinical dose is approximately 0.582 µg of DOTA-Siglec-9 per kg of body mass. This study demonstrates that iv administration of DOTA-Siglec-9 at a dose of 582 µg/kg was well tolerated in rats and did not produce toxicologically significant adverse effects.
基于肽的放射性化合物 [Ga]Ga-DOTA-Siglec-9 是一种用于正电子发射断层扫描成像炎症的新型药物。[Ga]Ga-DOTA-Siglec-9 的药物靶点是血管黏附蛋白 1。之前的研究已经在实验动物中使用 [Ga]Ga-DOTA-Siglec-9 获得了有希望的结果。然而，在将这种新型成像剂应用于临床试验之前，需要使用非放射性前体化合物 DOTA-Siglec-9 进行安全性和毒理学研究。这项扩展的单次剂量毒性研究旨在提供有关 DOTA-Siglec-9 的主要毒性作用的信息，并在大鼠单次静脉注射后指示可能的靶器官。该研究使用 60 只成年 Hsd：Sprague Dawley 大鼠进行，包括对照组和治疗组，以研究终浓度为 0.2mg/mL 的 DOTA-Siglec-9 溶液在单次静脉注射 582μg/kg 后的毒性。测试的最大剂量是基于欧洲药品管理局国际人用药品技术要求协调理事会指南 M3(R2)的毫克/千克基础上的临床剂量的 1000 倍。计划的临床剂量约为每公斤体重 0.582μg 的 DOTA-Siglec-9。本研究表明，在大鼠中静脉注射 582μg/kg 的 DOTA-Siglec-9 耐受性良好，未产生毒理学上显著的不良反应。
