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

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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.