PET probes for imaging of altered tryptophan metabolism in age-associated diseases

用于年龄相关疾病中色氨酸代谢改变成像的 PET 探针

• 批准号: 426635525
• 负责人: Professorin Dr. Heike Endepols
• 金额: --
• 依托单位: Institut für Radiochemie und Experimentelle Molekulare Bildgebung
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/426635525?language=en
• 关键词: PET; probes; imaging; altered; tryptophan

The aging of the population as a result of the higher life expectancy and the lower birth rate is seen now in almost all countries throughout the world. In Germany 27% of the population was over 60 years old in 2013. Because aging-associated disorders represent one of the main global challenges of the 21th century, novel methods for therapy and diagnostics of these diseases are needed. One of the main hallmarks of numerous age-related pathologies is an altered Trp metabolism. In neurodegenerative diseases such as Alzheimer's and Parkinson's disease, serotonin synthesis is often downregulated, while kynurenine metabolism is upregulated. In various tumors serotonin biosynthesis is strongly upregulated. This may obscure a parallel upregulation of kynurenine metabolism responsible for tumor escape. To develop an individual therapeutic strategy for each patient, pathological changes in both serotonin and kynurenine metabolism must be reliably differentiated from each other.Positron emission tomography (PET) is a powerful imaging tool enabling effective diagnosis of different pathologies at a very early stage even before clinical symptoms appear. PET imaging of Trp metabolism using 11C-labeled Trp analogues has been shown to improve the accuracy of primary diagnostics, staging and therapy follow-up of tumors and neurological disorders. Nevertheless, the short half-life of 11C (t1/2 = 20 min), as well as the laborious and time-consuming procedures for the preparation of these tracers impedes the implementation of Trp-PET in clinical practice. In contrast 18F possesses a half-life of 109 min which is more suitable for clinical and preclinical applications. Moreover, the longer half-life enables commercialization and widespread use of PET probes in medical centers without an own radiopharmaceutical unit within a satellite concept. Therefore, the main focus of this project is the development and preclinical evaluation of radiofluorinated probes for visualization of Trp metabolism.Our efforts will focus on the development of tracers which selectively target different steps of either the kynurenine pathway or serotonin synthesis and metabolism. The novel tracers will be studied first in vitro in appropriate tumor cell lines. Thereafter, the metabolic stability and in vivo biodistribution of the radiotracers will be initially examined in wild type rodents by quantitative dynamic imaging using a small animal PET scanner. Furthermore, the evaluation of the most promising candidates will be carried out in a Hemiparkinsonian rat model.This project will enable for the first time the selective visualization of serotonin biosynthesis and metabolism and KYN metabolic pathway in a preclinical model of age-associated diseases.

由于预期寿命延长和出生率降低而导致的人口老龄化，现在几乎在世界上所有国家都能看到。2013年，德国有27%的人口年龄在60岁以上。由于老龄化相关疾病是21世纪的主要全球挑战之一，因此需要新的治疗和诊断方法来治疗和诊断这些疾病。许多与年龄相关的病理的主要特征之一是色氨酸代谢的改变。在阿尔茨海默氏症和帕金森氏症等神经退行性疾病中，5-羟色胺合成通常被下调，而犬尿氨酸代谢则被上调。在各种肿瘤中，5-羟色胺的生物合成被强烈上调。这可能掩盖了与肿瘤逃逸有关的犬尿氨酸代谢的平行上调。要为每个患者制定个性化的治疗策略，必须可靠地区分5-羟色胺和犬尿氨酸代谢的病理变化。正电子发射断层扫描(PET)是一种强大的成像工具，能够在非常早期有效地诊断不同的病理，甚至在临床症状出现之前。使用11C标记的色氨酸类似物进行色氨酸代谢的PET成像已被证明可以提高肿瘤和神经系统疾病的初步诊断、分期和治疗随访的准确性。然而，11C的半衰期短(t1/2=20min)，以及制备这些示踪剂的繁琐和耗时的过程阻碍了Trp-PET在临床上的实施。相比之下，18F的半衰期为109分钟，更适合于临床和临床前应用。此外，较长的半衰期使PET探头能够商业化并在医疗中心广泛使用，而不是在卫星概念中拥有自己的放射性制药单元。因此，本项目的主要重点是显影Trp代谢的放射性氟化探针的开发和临床前评估。我们将致力于开发选择性靶向犬尿氨酸途径或5-羟色胺合成和代谢的不同步骤的示踪剂。新型示踪剂将首先在适当的肿瘤细胞系中进行体外研究。此后，放射性示踪剂的代谢稳定性和体内生物分布将首先通过使用小型动物PET扫描仪的定量动态成像在野生型啮齿动物中进行检测。此外，最有希望的候选者的评估将在偏侧帕金森病大鼠模型中进行。该项目将首次在年龄相关疾病的临床前模型中选择性地可视化5-羟色胺的生物合成和代谢以及KYN代谢途径。