Molecular imaging of purinergic signalling in cancer
While intracellular adenosine is a key molecule in energy metabolism, extracellular adenosine is a potent regulator of intracellular signaling affecting different physiological functions. The immunosuppressive effects of adenosine as well as the adenosine-triggered activation of catabolic energy production account for the pro-cancer roles of extracellular adenosine. Accordingly, adenosine receptors such as the A2B receptor – expressed on immune and endothelial cells only at elevated levels of adenosine – have been identified as potential new targets in cancer immunotherapy. Because the expression of the biological target in the patient is a prerequisite for response of targeted therapies, non-invasive assessment of the receptor expression and accessibility is essential. Accordingly, together with our partners of the University of Bonn and ROTOP Pharmaka GmbH, we designed and evaluated the first 18F-labelled radioligand for imaging the adenosine A2B receptor by PET.
The development of the new radioligand [18F]PA51 is based on a lead compound with a pyrazine scaffold, having a high affinity and selectivity towards this adenosine receptor subtype. Biodistribution and radiotracer metabolism of [18F]PA51 were assessed in mice to investigate the brain uptake and in vivo stability.
Besides, we apply our expertise in medicinal chemistry and radiochemistry to the development and validation of new radioligands of the adenosine A2A receptor. In a common research project with partners of the University of Dresden and ROTOP Pharmaka GmbH, we work on the investigation of alterations in adenosine receptor signaling by means of small animal PET/MRI studies in murine brain disease models.
- Pharma Center Bonn, University of Bonn (Prof. Christa E. Müller, Dr. Sonja Hinz)
- Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden (Prof. Richard H.W. Funk, Prof. Heinz Reichmann, Dr. Francisco Pan-Montojo)
- ROTOP Pharmaka GmbH, Dresden (Jens Junker, Dr. Cathleen Juhl)
- Universität Leipzig (PD Dr. Ute Krügel)
- Friedrich Schiller University Jena (Prof. Carsten Hoffmann)
- BMBF (German Federal Ministry for Education and Research) within the BioPharma initiative “Neuroallianz”
- EFRE (European Regional Development Fund) together with the Free State of Saxony
- Lindemann M, Hinz S, Deuther-Conrad W, Dukic-Stefanovic S, Teodoro R, Toussaint M, Kranz M, Juhl C, Steinbach J, Brust P, Müller CE, Wenzel B. Radiosynthesis and in vivo evaluation of a fluorine-18 labeled pyrazine based radioligand for PET imaging of the adenosine A2B receptor. Bioorg Med Chem 2018,
- Lindemann M, Wenzel B, Hinz S, Dukic-Stefanovic S, Deuther-Conrad W, Teodoro R, Juhl C, Müller C, Brust P, Steinbach J. Development of the first fluorine-18 labelled radioligand for imaging of the adenosine A2B receptor. J Labelled Comp Radiopharm 2017, 60 (S1), Molecules 2018; 23(3), pii: E702.
Lindemann M, Wenzel B, Hinz S, Dukic-Stefanovic S, Deuther-Conrad W, Teodoro R, Juhl C, Müller C, Brust P, Steinbach J. Entwicklung des ersten F-18-markierten Radioliganden zur molekularen Bildgebung des Adenosinrezeptors A2B im Gehirn. Nuklearmedizin 2017, 56(2), A45