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

由于预期寿命增加和出生率降低，世界上几乎所有国家都出现了人口老龄化。2013年，德国有27%的人口年龄超过60岁。由于衰老相关疾病代表了21世纪世纪的主要全球挑战之一，因此需要用于治疗和诊断这些疾病的新方法。许多与年龄相关的病理的主要标志之一是改变的Trp代谢。在神经退行性疾病如阿尔茨海默病和帕金森病中，5-羟色胺合成通常下调，而犬尿氨酸代谢上调。在各种肿瘤中，5-羟色胺生物合成强烈上调。这可能掩盖了负责肿瘤逃逸的犬尿氨酸代谢的平行上调。为了给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，即使在临床症状出现之前，也能在非常早期的阶段有效地诊断不同的病理。使用11 C标记的Trp类似物进行的Trp代谢PET成像已被证明可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，11 C的短半衰期（t1/2 = 20 min）以及用于制备这些示踪剂的费力且耗时的程序阻碍了Trp-PET在临床实践中的实施。相比之下，18F的半衰期为109分钟，更适合临床和临床前应用。此外，较长的半衰期使得PET探针能够在卫星概念内没有自己的放射性药物单元的医疗中心中商业化和广泛使用。因此，本项目的主要重点是开发和临床前评价用于可视化Trp代谢的放射性氟化探针。我们的努力将集中在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的开发上。新的示踪剂将首先在适当的肿瘤细胞系中进行体外研究。此后，将使用小动物PET扫描仪通过定量动态成像在野生型啮齿动物中初步检查放射性示踪剂的代谢稳定性和体内生物分布。此外，最有前途的候选人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。

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.